KR20240017118A - Macrocycles with hetrocyclic p2' groups as factor xia inhibitors - Google Patents

Abstract

상기 식에서 모든 가변기는 본원에 정의된 바와 같다.The present invention provides compounds of formula (I) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof. These compounds are selective factor XIa inhibitors, or dual inhibitors of FXIa and plasma kallikrein. The present invention also relates to pharmaceutical compositions comprising these compounds and methods of using them to treat thromboembolic and/or inflammatory disorders.
<Formula I>

All variables in the above formula are as defined herein.

Description

MACROCYCLES WITH HETROCYCLIC P2' GROUPS AS FACTOR XIA INHIBITORS}

Cross-reference to related applications

This application is filed under 35 U.S.C. §119(e), claim priority to U.S. Provisional Patent Application No. 61/933,942, filed January 31, 2014, and U.S. Provisional Patent Application No. 62/058,293, filed October 1, 2014, which are hereby incorporated by reference in their entirety. It is incorporated herein by reference.

field of invention

The present invention generally relates to novel macrocyclic compounds and analogues thereof that are factor XIa inhibitors or dual inhibitors of factor or methods of use thereof for the treatment of retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

Thromboembolic diseases are prevalent in developed countries despite the availability of anticoagulants such as warfarin (COUMADIN®), heparin, low molecular weight heparin (LMWH) and synthetic pentasaccharides and antiplatelet agents such as aspirin and clopidogrel (PLAVIX®). It remains a leading cause of death. The oral anticoagulant warfarin inhibits the post-translational maturation of coagulation factors VII, IX, However, its use is limited by its narrow therapeutic index, slow onset of therapeutic effect, numerous dietary and drug interactions, and the need for monitoring and dose adjustment. Therefore, it is becoming increasingly important to discover and develop safe and effective oral anticoagulants for the prevention and treatment of a wide range of thromboembolic disorders.

One approach is to inhibit thrombin generation by targeting inhibition of coagulation factor XIa (FXIa). Factor The resulting TF:FVIIa complex activates Factor IX (FIX) and Factor X (FX), leading to the production of Factor Xa (FXa). The resulting FXa catalyzes the conversion of prothrombin to minor thrombin, and this pathway is subsequently blocked by tissue factor pathway inhibitor (TFPI). The process of coagulation is then further propagated through feedback activation of factors V, VIII and XI by catalytic amounts of thrombin. (Gailani, D. et al., Arterioscler. Thromb. Vasc. Biol., 27:2507-2513 (2007).) The burst of thrombin generated converts fibrinogen to fibrin, which polymerizes and forms the structural framework of the thrombus. forms and activates platelets, the main cellular component of coagulation (Hoffman, M., Blood Reviews, 17:S1-S5 (2003)). Therefore, factor XIa plays a major role in propagating this amplification loop and is therefore an attractive target for antithrombotic therapy.

An alternative mode of initiation of coagulation operates when blood is exposed to an artificial surface. This process is also named contact activation. Surface absorption of factor XII causes a conformational change in the factor XII molecule, thereby facilitating activation to proteolytically active factor XII molecules (factor Factor XIIa (or XIIf) has multiple target proteins, including plasma prekallikrein and factor XI.

Plasma prekallikrein is the zymogen of trypsin-like serine protease and is present in plasma at 35 to 50 μg/mL. The gene structure is similar to that of factor XI. Overall, the amino acid sequence of plasma kallikrein has 58% homology to factor XI. Plasma kallikrein is thought to play a role in a number of inflammatory disorders. The major inhibitor of plasma kallikrein is the serpin C1 esterase inhibitor. Patients with a genetic deficiency in the C1 esterase inhibitor suffer from hereditary angioedema (HAE), which causes intermittent swelling of the face, hands, throat, gastrointestinal tract, and genitals. Blisters that form during acute episodes contain high levels of plasma kallikrein, which cleaves high molecular weight kininogen, liberating bradykinin, leading to increased vascular permeability. Treatment with the larger protein plasma kallikrein inhibitors has been shown to effectively treat HAE by preventing the release of bradykinin, which causes increased vascular permeability (Lehmann, A., “Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery", Expert Opin. Biol. Ther., 8:1187-1199 (2008)).

The plasma kallikrein-kinin system is abnormally abundant in patients with advanced diabetic macular edema. It has recently been revealed that plasma kallikrein contributes to retinal vascular dysfunction in diabetic rats (Clermont, A. et al., "Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats", Diabetes, 60:1590-1598 (2011)). Moreover, administration of the plasma kallikrein inhibitor ASP-440 improved both retinal vascular permeability and retinal blood flow abnormalities in diabetic rats. Therefore, plasma kallikrein inhibitors may have utility as a treatment for reducing retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema. Other complications of diabetes such as cerebral hemorrhage, nephropathy, cardiomyopathy and neuropathy, all of which are associated with plasma kallikrein, can also be considered targets for plasma kallikrein inhibitors.

To date, no small molecule synthetic plasma kallikrein inhibitor has been approved for medical use. Large protein plasma kallikrein inhibitors carry a risk of anaphylactic reaction, as reported for Ecallantide. Therefore, there remains a need for orally available compounds that inhibit plasma kallikrein, do not cause anaphylaxis. Furthermore, molecules in the known art feature highly polar and ionizable guanidine or amidine functional groups. It is well known that these functional groups may limit digestive tract permeability and therefore oral availability.

The present invention provides novel macrocyclic compounds, analogs thereof, such as stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof, useful as selective factor XIa inhibitors or dual inhibitors of factor XIa and plasma kallikrein.

The present invention also provides methods and intermediates for preparing the compounds of the present invention.

The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of a compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

The compounds of the invention can be used for the treatment and/or prevention of thromboembolic disorders.

The compounds of the present invention can be used in the treatment of retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

Compounds of the invention can be used in therapy.

The compounds of the invention can be used for the manufacture of medicaments for the treatment and/or prevention of thromboembolic disorders.

The compounds of the invention can be used alone, in combination with other compounds of the invention, or in combination with one or more, preferably 1 to 2, other agent(s).

These and other features of the invention will be presented in expanded form as the disclosure continues.

I. Compounds of the present invention

In one aspect, the invention provides, inter alia, a compound of formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

<Formula I>

In the above equation

Ring A is independently selected from 6-membered aryl and 5- to 6-membered heterocyclyl, wherein said aryl and heterocyclyl are optionally substituted with one or more R ⁴ as valency permits;

Ring B is a 5- to 10-membered heterocyclyl optionally substituted with one or more R ³ as valency permits, or a carbon atom and from N, NR ^3c , O, and S(O) _p selected is a 5- to 10-membered heterocyclyl containing 1-4 heteroatoms, optionally substituted with one or more R ³ where valency permits;

G ¹ is independently selected from C _3-10 carbocyclyl and 5- to 10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with one or more R ⁸ where valence permits. become;

X is independently selected from C _4-8 alkylene and C _4-8 alkenylene, wherein the alkylene and alkenylene are substituted by R ¹ and R ² ; Alternatively, one or more of the carbon atoms of the alkylene and alkenylene may be replaced by O, C=O, S(=O) _p , S(=O) _p NH, and NR ¹⁵ ;

Y is independently -CR ¹³ NH-, -NHC(=O)-, -C(=O)NH-, -S(=O) _p NH-, -NHS(=O) _p -, and C _{1- 2} is selected from alkylene;

R ¹ and R ² are independently H, D, halogen, haloalkyl, C _1-6 alkyl (optionally substituted with R ⁶ ), hydroxyl, and alkoxy optionally substituted with R ⁶ , and optionally substituted with R ⁶ is selected from C _3-6 cycloalkyl; Optionally, when R ¹ and R ² are attached to the same carbon atom, together they form an oxo group or C _3-6 cycloalkyl; Optionally, when R ¹ and R ² are attached to carbon atoms adjacent to each other, together they form a bond or carbocyclyl; Optionally, R ¹ and R ¹⁵ or R ² and R ¹⁵ are taken together to form a ring;

R ³ is independently H, NO ₂ , =O, halogen, haloalkyl, C _1-4 alkyl (optionally substituted with R ⁶ ), C _2-4 alkenyl (optionally substituted with R ⁶ ), C _{2- 4} alkynyl (optionally substituted with R ⁶ ), CN, -(CH ₂ ) _n -OR ⁵ , -(CH ₂ ) _n -NR ⁵ R ⁵ , -(CH ₂ ) _n -C(=O)R ⁵ , -(CH ₂ ) _n -C(=O)OR ⁵ , -(CH ₂ ) _n -NR ⁹ C(=O)OR ⁵ , -(CH ₂ ) _n -NR ⁹ C(=O)R ⁵ , -(CH ₂ ) _n -NR ⁹ C(N-CN)NHR ⁵ , -(CH ₂ ) _n -NR ⁹ C(NH)NHR ⁵ , -(CH ₂ ) _n -N=CR ⁹ NR ⁵ R ⁵ , -(CH ₂ ) _n -NR ⁹ C(=O)NR ⁵ R ⁵ , -(CH ₂ ) _n -C(=O)NR ⁵ R ⁵ , -(CH ₂ ) _n -NR ⁹ C(=S) NR ⁹ C(=O)R ⁵ , -(CH ₂ ) _n -S(=O) _p R ⁵ , -(CH ₂ ) _n -S(=O) _p NR ⁵ R ⁵ , -(CH ₂ ) _n -NR ⁹ S(=O) _p NR ⁵ R ⁵ , -(CH ₂ ) _n -NR ⁹ S(=O) _p R ⁵ , -(CH ₂ ) _n -C _3-10 carbocyclyl and -(CH ₂ ) is selected from _n -4- to 10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with R ⁶ ; Optionally, two adjacent R ³ groups on the heterocyclyl may form a ring optionally substituted with R ⁶ ;

R ^3c is independently H, haloalkyl, C _1-4 alkyl (optionally substituted with R ⁶ ), -(CH ₂ ) _1-2 -OH, C(=O)C _1-4 alkyl, -(CH ₂ ) _0-2 -C(=O)OH, -C(=O)OC _1-4 alkyl, S(=O) _p C _1-6 alkyl, -(CH ₂ ) _n -C _3-10 carbocyclyl and -(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein the carbocyclyl and heterocyclyl are optionally substituted with R ⁶ ;

R ⁴ is independently H, OH, NH ₂ , halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, -CH ₂ OH, -C(=O)OH, -CH ₂ C(=O)OH, -CO ₂ (C _1-4 alkyl), -C(=O)NH ₂ , -C(=O)NH(C _1-4 alkyl), -C(=O)N (C _1-4 alkyl) ₂ , -S(=O) ₂ C _1-4 alkyl, -S(=O) ₂ NH ₂ , C _3-6 cycloalkyl, aryl, and 5- to 6-membered heterocycle selected from ryl, wherein said cycloalkyl, aryl and heterocyclyl are optionally substituted with R ⁶ ;

R ⁵ is independently H, C _1-4 alkyl (optionally substituted with halogen, hydroxyl, alkoxy, carboxy, hydroxycarbonyl, alkoxycarbonyl, amino, substituted amino), -(CH ₂ ) _n -C is selected from _3-10 carbocyclyl and -(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with R ⁶ ; Alternatively, R ⁵ and R ⁵ together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with R ⁶ ;

R ⁶ is independently H, -(CH ₂ ) _n -OH, =O, -(CH ₂ ) _n NH ₂ , -(CH ₂ ) _n CN, halogen, C _1-6 alkyl, -(CH ₂ ) _n -C(=O)OH, -(CH ₂ ) _n -C(=O)NH ₂ , -(CH ₂ ) _n -C(=O)OC _1-4 alkyl, -(CH ₂ ) _n -OC _{1 -4} alkyl, -(CH ₂ ) _n -C _3-10 carbocyclyl, -(CH ₂ ) _n -4- to 10-membered heterocyclyl, and -O-4- to 10-membered heterocyclyl selected, wherein said carbocyclyl and heterocyclyl are optionally substituted with R ¹⁰ ;

R ⁷ is independently selected from H, hydroxyl, alkoxy, halogen, amino, C _1-3 haloalkyl, and C _1-3 alkyl;

R ⁸ is independently H, halogen, -(CH ₂ ) _n CN, C _1-6 alkyl, amino, aminoalkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, alkylcarbonyl, carboxyl, carboxyl ester, Amide, haloalkylaminocarbonyl, arylalkylaminocarbonyl, haloalkylaminocarbonyl, alkoxycarbonylamino, haloalkylcarbonylamino, arylamino, heteroarylamino, arylalkylcarbonyl, aryloxy, heteroaryloxy, Alkylthio, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfonamide, -(CH ₂ ) _n -aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl, and -(CH ₂ ) _n - selected from 4- to 12-membered heterocyclyl, wherein said aryl, cycloalkyl, and heterocyclyl are optionally substituted with R ¹⁰ ;

Alternatively, two adjacent R ⁸ groups together form a heterocyclic ring optionally substituted with R ¹⁰ ;

R ⁹ is H or C _1-6 alkyl;

R ¹⁰ is independently H, C _1-6 alkyl (optionally substituted with R ¹¹ ), C _2-6 alkenyl, C _2-6 alkynyl, aryl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -O-4- to 10-membered heterocyclyl (optionally substituted with R ¹¹ ), halogen, -(CH ₂ ) _n CN, NO ₂ , =O, C(=O)NR ¹² R ¹² , -(CH ₂ ) _n C(=O)OR ¹² , Si(C _1-4 alkyl) ₃ , -(CH ₂ ) _n -OR ¹² , -(CH ₂ ) _n -NR ¹² R ¹² , -S(=O) _p C _1-6 alkyl, NR ¹² S(=O) _p C _1-6 alkyl, S(=O) _p NR ¹² R ¹² , and C(=NOH)NH ₂ ;

R ¹¹ at each occurrence is independently selected from H, halogen, C _1-5 alkyl, -(CH ₂ ) _n -OH, C _3-6 cycloalkyl, phenyl, and heterocyclyl;

R ¹² at each occurrence is independently selected from H, C _1-5 alkyl optionally substituted with R ¹¹ , C _3-6 cycloalkyl, phenyl, and heterocyclyl, or R ¹² and R ¹² are both together with the nitrogen atom to which it is attached forms a heterocyclic ring optionally substituted with C _1-4 alkyl;

R ¹³ is independently, in each case, H, C _1-4 haloalkyl, C _1-4 alkyl, C(=O)OH, C(=O)O(C _1-4 alkyl), C(=O) O(CH ₂ ) ₂ O(C _1-4 alkyl), C(=O)O(C _1-4 haloalkyl), CH ₂ C(=O)OH, CH ₂ C(=O)O(C _{1 -4} alkyl), C(=O)NH ₂ , C(=O)NH(C _1-4 alkyl), C(=O)N(C _1-4 alkyl) ₂ , and -C(=O)NH (C _1-4 alkoxy);

R ¹⁵ is H or C _1-6 alkyl;

n is, in each case, an integer independently selected from 0, 1, 2, 3, and 4;

p is, in each case, an integer independently selected from 0, 1, and 2.

In another aspect, the present invention

Ring A is independently selected from 6-membered aryl and 5- to 6-membered heterocycle, wherein said aryl and heterocycle are optionally substituted with one or more R ⁴ as valence permits;

Ring B has one or more R ³ if valency permits randomly substituted is a 5- to 10-membered heterocycle;

G ¹ is independently selected from C _3-10 carbocycles and 5- to 10-membered heterocycles, wherein said carbocycles and heterocycles are optionally substituted with one or more R ⁸ as valency permits;

X is independently selected from C _4-8 alkylene and C _4-8 alkenylene, wherein the alkylene and alkenylene are substituted by R ¹ and R ² ; Alternatively, one or more of the carbon atoms of the alkylene and alkenylene may be substituted by O, C=O, S(=O) _p , S(=O) _p NH, NH, and N(C _1-4 alkyl). can be replaced;

Y is independently -CR ¹³ NH-, -NHC(=O)-, -C(=O)NH-, -S(=O) _p NH-, -NHS(=O) _p -, and C _{1- 2} is selected from alkylene;

R ¹ and R ² are independently optionally substituted with H, halogen, haloalkyl, C _1-6 alkyl (optionally substituted with R ⁶ ), hydroxyl, and alkoxy (optionally substituted with R ⁶ ), and R ⁶ is selected from C _3-6 cycloalkyl; Optionally, when R ¹ and R ² are attached to the same carbon atom, together they form an oxo group or C _3-6 cycloalkyl; Optionally, when R ¹ and R ² are attached to carbon atoms adjacent to each other, together they form a bond or carbocycle;

R ³ is independently H, NO ₂ , =O, halogen, haloalkyl, C _1-4 alkyl (optionally substituted with R ⁶ ), C _2-4 alkenyl (optionally substituted with R ⁶ ), C _{2- 4} alkynyl (optionally substituted with R ⁶ ), CN, -(CH ₂ ) _n -OR ⁵ , -(CH ₂ ) _n -NR ⁵ R ⁵ , -(CH ₂ ) _n -C(=O)R ⁵ , -(CH ₂ ) _n -C(=O)OR ⁵ , -(CH ₂ ) _n -NR ⁹ C(=O)OR ⁵ , -(CH ₂ ) _n -NR ⁹ C(=O)R ⁵ , -(CH ₂ ) _n -NR ⁹ C(N-CN)NHR ⁵ , -(CH ₂ ) _n -NR ⁹ C(NH)NHR ⁵ , -(CH ₂ ) _n -N=CR ⁹ NR ⁵ R ⁵ , -(CH ₂ ) _n -NR ⁹ C(=O)NR ⁵ R ⁵ , -(CH ₂ ) _n -C(=O)NR ⁵ R ⁵ , -(CH ₂ ) _n -NR ⁹ C(=S) NR ⁹ C(=O)R ⁵ , -(CH ₂ ) _n -S(=O) _p C _1-6 alkyl, optionally substituted with R ¹¹ , -(CH ₂ ) _n -S(=O) _p NR ⁵ R ⁵ , -(CH ₂ ) _n -NR ⁹ S(=O) _p NR ⁵ R ⁵ , -(CH ₂ ) _n -NR ⁹ S(=O) _p C _1-6 alkyl, optionally substituted with R ¹¹ ; -(CH ₂ ) _n -C _3-10 carbocycle and -(CH ₂ ) _n -4- to 10-membered heterocycle, wherein said carbocycle and heterocycle are optionally substituted with R ⁶ ; Optionally, two adjacent R ³ groups on the carbocycle and heterocycle may form a ring optionally substituted with R ⁶ ;

R ⁴ is independently H, OH, NH ₂ , halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, -CH ₂ OH, -C(=O)OH, -CH ₂ C(=O)OH, -CO ₂ (C _1-4 alkyl), -C(=O)NH ₂ , -C(=O)NH(C _1-4 alkyl), -C(=O)N (C _1-4 alkyl) ₂ , -S(=O) ₂ C _1-4 alkyl, S(=O) ₂ NH ₂ , C _3-6 cycloalkyl, aryl, and 5- to 6-membered heterocycle selected, wherein the cycloalkyl, aryl and heterocycle are optionally substituted with R ⁶ ;

R ⁵ is independently H, C _1-4 alkyl (optionally substituted with halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino, substituted amino), -(CH ₂ ) _n -C _3-10 carbo cycle and -(CH ₂ ) _n -4- to 10-membered heterocycle, wherein the carbocycle and heterocycle are optionally substituted with R ⁶ ; Alternatively, R ⁵ and R ⁵ together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with R ⁶ ;

R ⁶ is independently H, -(CH ₂ ) _n -OH, =O, -(CH ₂ ) _n NH ₂ , -(CH ₂ ) _n CN, halogen, C _1-6 alkyl, -(CH ₂ ) _n -C(=O)OH, -(CH ₂ ) _n -C(=O)OC _1-4 alkyl, -(CH ₂ ) _n -OC _1-4 alkyl, -(CH ₂ ) _n -C _3-10 selected from carbocycle, -(CH ₂ ) _n -4- to 10-membered heterocycle, and -O-4- to 10-membered heterocycle, wherein said carbocycle and heterocycle are optionally substituted with R ¹⁰ become;

R ⁷ is independently selected from H, hydroxyl, alkoxy, halogen, amino, and C _1-3 alkyl;

R ⁸ is independently H, halogen, CN, NH ₂ , C _1-6 alkyl, haloalkyl, haloalkylcarbonylamine, alkylcarbonyl, hydroxyl, alkoxy, haloalkoxy, -(CH ₂ ) _n -aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl, and -(CH ₂ ) _n -4- to 6-membered heterocycle, wherein the aryl, cycloalkyl, and heterocycle are optionally substituted with R ¹⁰ become;

Alternatively, two adjacent R ⁸ groups form a heterocyclic ring optionally substituted with R ¹⁰ ;

R ⁹ is H or C _1-6 alkyl;

R ¹⁰ is independently H, C _1-6 alkyl (optionally substituted with R ¹¹ ), C _2-6 alkenyl, C _2-6 alkynyl, aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -O-4- to 10-membered heterocycle (optionally substituted with R ¹¹ ), halogen, CN, NO ₂ , =O, C(=O) NR ¹² R ¹² , C(=O)OH, Si(C _1-4 alkyl) ₃ , -(CH ₂ ) _n -OR ¹² , -(CH ₂ ) _n -NR ¹² R ¹² , and C(=NOH) is selected from NH ₂ ;

R ¹¹ at each occurrence is independently selected from H, halogen, C _1-5 alkyl, -(CH ₂ ) _n -OH, C _3-6 cycloalkyl, phenyl, and heterocycle;

R ¹² at each occurrence is independently selected from H, C _1-5 alkyl, C _3-6 cycloalkyl, phenyl, and heterocycle, or R ¹² and R ¹² together with the nitrogen atom to which they are both attached forming a heterocyclic ring optionally substituted with C _1-4 alkyl;

R ¹³ is independently at each occurrence H, halogen, C _1-4 haloalkyl, CO ₂ H, CO ₂ (C _1-4 alkyl), CO ₂ (CH ₂ ) ₂ O(C _1-4 alkyl), CO ₂ (C _1-4 haloalkyl), CO ₂ (CH ₂ ) ₂ SO ₂ (C _1-4 alkyl), CH ₂ CO ₂ H, CH ₂ CO ₂ (C _1-4 alkyl), CONH ₂ , CONH (C _1-4 alkyl), CON(C _1-4 alkyl) ₂ , -CONH(C _1-4 alkoxy), -CO ₂ (CH ₂ ) ₂ O(C _1-4 alkyl), -CO ₂ (CH ₂ ) ₂ N(C _1-4 alkyl) ₂ , -CONH(CH ₂ ) ₂ O(C _1-4 alkyl), -CONH(CH ₂ ) ₂ N(C _1-4 alkyl) ₂ , -CON(C _1-4 alkyl)(CH ₂ ) ₂ O(C _1-4 alkyl), -CON(C _1-4 alkyl)(CH ₂ ) ₂ N(C _1-4 alkyl) ₂ , C _1-4 alkyl, - CONHBn, -CONH(OBn), -(CO) _0-1 (CH ₂ ) _0-3 -C _3-6 carbocycle, and -(CH ₂ ) _0-1 -(CO) _0-1 -(V ) _0-1 -(CH ₂ ) _0-2 -(4 containing a carbon atom and 1-4 heteroatoms selected from N, NH, N(C _1-4 alkyl), O, and S(O) _p - to 6-membered heterocycle), wherein the carbocycle and heterocycle are substituted with 0-2 R ¹⁴ ;

R ¹⁴ is independently at each occurrence, halogen, OH, CHF ₂ , CF ₃ , C _1-4 alkoxy, CH ₂ OH, CO ₂ H, CO ₂ (C _1-4 alkyl), CONH ₂ , and C _{1- 4} selected from the group consisting of alkyl;

V is independently selected from O, NH and N(C _1-4 alkyl);

n is, in each instance, an integer independently selected from 0, 1, 2, 3, and 4;

where p is, in each case, an integer independently selected from 0, 1, and 2.

Provided are compounds of Formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

In another aspect, the present invention

Ring A is independently selected from 6-membered aryl and 5- to 6-membered heterocycle, wherein said aryl and heterocycle are optionally substituted with one or more R ⁴ as valence permits;

Ring B is a 5- to 10-membered heterocycle optionally substituted with one or more R ³ where valency permits;

G ¹ is independently selected from C _3-10 carbocycles and 5- to 10-membered heterocycles, wherein said carbocycles and heterocycles are optionally substituted with one or more R ⁸ as valency permits;

X is independently selected from C _4-8 alkylene and C _4-8 alkenylene, wherein the alkylene and alkenylene are substituted by R ¹ and R ² ; Alternatively, one or more of the carbon atoms of the alkylene and alkenylene may be replaced by O, C=O, S(O) _p , S(O) _p NH, NH, and N(C _1-4 alkyl). can;

Y is independently selected from -NH-C(O)- and -C(O)-NH-;

R ¹ and R ² are independently H, halogen, haloalkyl, C _1-6 alkyl (optionally substituted with R ⁶ ), hydroxyl, and alkoxy (optionally substituted with R ⁶ ), and optionally substituted with R ⁶ is selected from C _3-6 cycloalkyl; Optionally, when R ¹ and R ² are attached to the same carbon atom, together they form an oxo group or C _3-6 cycloalkyl; Optionally, when R ¹ and R ² are attached to carbon atoms adjacent to each other, together they form a bond or carbocycle;

R ³ is independently H, NO ₂ , =O, halogen, haloalkyl, C _1-4 alkyl (optionally substituted with R ⁶ ), C _2-4 alkenyl (optionally substituted with R ⁶ ), C _{2- 4} alkynyl (optionally substituted with R ⁶ ), CN, -(CH ₂ ) _n -OR ⁵ , -(CH ₂ ) _n -NR ⁵ R ⁵ , -(CH ₂ ) _n -C(O)OR ⁵ , -(CH ₂ ) _n -NR ⁹ C(O)OR ⁵ , -(CH ₂ ) _n -NR ⁹ C(O)R ⁵ , -(CH ₂ ) _n -NR ⁹ C(N-CN)NHR ⁵ , -(CH ₂ ) _n -NR ⁹ C(NH)NHR ⁵ , -(CH ₂ ) _n -N=CR ⁹ NR ⁵ R ⁵ , -(CH ₂ ) _n -NR ⁹ C(O)NR ⁵ R ⁵ , -(CH ₂ ) _n -C(O)NR ⁵ R ⁵ , -(CH ₂ ) _n -NR ⁹ C(S)NR ⁹ C(O)R ⁵ , -(CH ₂ ) _n -S(O) _p R ¹² , -(CH ₂ ) _n -S(O) _p NR ⁵ R ⁵ , -(CH ₂ ) _n -NR ⁹ S(O) _p NR ⁵ R ⁵ , -(CH ₂ ) _n -NR ⁹ S( O) _p R ¹² , -(CH ₂ ) _n -C _3-10 carbocycle and -(CH ₂ ) _n -4- to 10-membered heterocycle, wherein said carbocycle and heterocycle are R optionally substituted with ⁶ ; Optionally, two adjacent R ³ groups on the carbocycle and heterocycle may form a ring optionally substituted with R ⁶ ;

R ⁴ is independently H, OH, NH ₂ , halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, -CH ₂ OH, -CO ₂ H, -CH ₂ CO ₂ H, -CO ₂ (C _1-4 alkyl), -C(O)NH ₂ , -C(O)NH(C _1-4 alkyl), -C(O)N(C _1-4 alkyl) ₂ , S(O) ₂ NH ₂ , C _3-6 cycloalkyl, aryl, and 5- to 6-membered heterocycle, wherein the cycloalkyl, aryl, and heterocycle are optionally substituted with R ⁶ ;

R ⁵ is independently H, C _1-4 alkyl (optionally substituted with halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino, substituted amino), -(CH ₂ ) _n -C _3-10 carbo cycle and -(CH ₂ ) _n -4- to 10-membered heterocycle, wherein the carbocycle and heterocycle are optionally substituted with R ⁶ ; Alternatively, R ⁵ and R ⁵ together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with R ⁶ ;

R ⁶ is independently H, -(CH ₂ ) _n -OH, =O, -(CH ₂ ) _n NH ₂ , -(CH ₂ ) _n CN, halogen, C _1-6 alkyl, -(CH ₂ ) _n -C(=O)OH, -(CH ₂ ) _n -C(=O)OC _1-4 alkyl, -(CH ₂ ) _n -OC _1-4 alkyl, -(CH ₂ ) _n -C _3-10 selected from carbocycle, -(CH ₂ ) _n -4- to 10-membered heterocycle, and -O-4- to 10-membered heterocycle, wherein said carbocycle and heterocycle are optionally substituted with R ¹⁰ become;

R ⁷ is independently selected from H, hydroxyl, alkoxy, halogen, amino, and C _1-3 alkyl;

R ⁸ is independently H, halogen, CN, NH ₂ , C _1-6 alkyl, haloalkyl, haloalkylcarbonylamine, alkylcarbonyl, alkoxy, haloalkoxy, -(CH ₂ ) _n -aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl, and -(CH ₂ ) _n -4- to 6-membered heterocycle;

R ⁹ is H or C _1-6 alkyl;

R ¹⁰ is independently H, C _1-6 alkyl (optionally substituted with R ¹¹ ), C _2-6 alkenyl, C _2-6 alkynyl, -(CH ₂ ) _n -C _3-6 cycloalkyl (R optionally substituted with ¹¹ ), -O-4- to 10-membered heterocycle (optionally substituted with R ¹¹ ), F, Cl, Br, CN, NO ₂ , =O, CO ₂ H, -(CH ₂ ) is selected from _n -OC _1-5 alkyl, -(CH ₂ ) _n -OR ¹¹ , and -(CH ₂ ) _n -NR ¹¹ R ¹¹ ;

R ¹¹ at each occurrence is independently selected from H, C _1-5 alkyl, -(CH ₂ ) _n -OH, C _3-6 cycloalkyl, and phenyl, or R ¹¹ and R ¹¹ are both attached. Together with the nitrogen atom to which it is located, it forms a heterocyclic ring optionally substituted with C _1-4 alkyl;

R ¹² is C _1-6 alkyl optionally substituted with R ¹¹ ;

n is, in each instance, an integer independently selected from 0, 1, 2, 3, and 4;

where p is, in each case, an integer independently selected from 0, 1, and 2.

Provided are compounds of Formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

In another aspect, the invention provides a compound of Formula II or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

<Formula II>

In the above equation

Ring A is independently selected from 6-membered aryl and 5- to 6-membered heterocycle, wherein said aryl and heterocycle are substituted with 1-4 occurrences of R ⁴ ;

Ring B is a 5- to 10-membered heterocycle substituted with 1-4 R ³ ;

G ¹ is independently selected from C _3-10 carbocycle and 5- to 10-membered heterocycle, wherein said carbocycle and heterocycle are substituted with 1-4 R ⁸ ;

Y is independently selected from -NH-C(O)- and -C(O)-NH-;

R ¹ and R ² are independently H, halogen, haloalkyl, C _1-4 alkyl (optionally substituted with R ⁶ ), hydroxyl, and alkoxy (optionally substituted with R ⁶ ), and optionally substituted with R ⁶ is selected from C _3-5 cycloalkyl;

R ³ is independently H, =O, halogen, haloalkyl, C _1-4 alkyl (optionally substituted with R ⁶ ), C _2-4 alkenyl (optionally substituted with R ⁶ ), C _2-4 alkynyl (optionally substituted with R ⁶ ), CN, NO ₂ , -(CH ₂ ) _n -OR ⁵ , -(CH ₂ ) _n -NR ⁵ R ⁵ , -(CH ₂ ) _n -C(O)OR ⁵ , -(CH ₂ ) _n -NR ⁹ C(O)OR ⁵ , -(CH ₂ ) _n -NR ⁹ C(O)R ⁵ , -(CH ₂ ) _n -NR ⁹ C(N-CN)NHR ⁵ , -(CH ₂ ) _n -NR ⁹ C(NH)NHR ⁵ , -(CH ₂ ) _n -N=CR ⁹ NR ⁵ R ⁵ , -(CH ₂ ) _n -NR ⁹ C(O)NR ⁵ R ⁵ , -(CH ₂ ) _n -C(O)NR ⁵ R ⁵ , -(CH ₂ ) _n -NR ⁹ C(S)NR ⁹ C(O)R ⁵ , -(CH ₂ ) _n -S(O) _p R ¹² , -(CH ₂ ) _n -S(O) _p NR ⁵ R ⁵ , -(CH ₂ ) _n -NR ⁹ S(O) _p NR ⁵ R ⁵ , -(CH ₂ ) _n -NR ⁹ S( O) _p R ¹² , -(CH ₂ ) _n -C _3-10 carbocycle and -(CH ₂ ) _n -4- to 10-membered heterocycle, wherein said carbocycle and heterocycle are R optionally substituted with ⁶ ; Optionally, two adjacent R ³ groups on the carbocycle and heterocycle may form a ring optionally substituted with R ⁶ ;

R ⁴ is independently H, OH, halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, -C(O)NH ₂ , -C(O)NH(C _{1- 4} alkyl), -C(O)N(C _1-4 alkyl) ₂ , C _3-6 cycloalkyl, aryl, and 5- to 6-membered heterocycle, wherein said cycloalkyl, aryl, and heterocycle is optionally substituted with R ⁶ ;

R ⁵ is independently H, C _1-4 alkyl (optionally substituted with halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino, substituted amino), C _3-10 carbocycle and 4- to 10- selected from a heterocycle, wherein the carbocycle and heterocycle are optionally substituted with R ⁶ ; Alternatively, R ⁵ and R ⁵ together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with R ⁶ ;

R ⁶ is independently OH, =O, -(CH ₂ ) _n NH ₂ , -(CH ₂ ) _n CN, halogen, C _1-6 alkyl, -(CH ₂ ) _n -C(=O)OH, - (CH ₂ ) _n -C(=O)OC _1-4 alkyl, -(CH ₂ ) _n -OC _1-4 alkyl, -(CH ₂ ) _n -C _3-10 carbocycle, -(CH ₂ ) is selected from _n -4- to 10-membered heterocycle, and -(CH ₂ ) _n -4- to 10-membered heterocycle, wherein said carbocycle and heterocycle are optionally substituted with R ¹⁰ ;

R ⁷ is independently selected from H, hydroxyl, alkoxy, halogen, methyl, ethyl, and isopropyl;

R ⁸ is independently H, halogen, CN, NH ₂ , C _1-6 alkyl, haloalkyl, alkylcarbonyl, alkoxy, haloalkoxy, -(CH ₂ ) _n -aryl, -(CH ₂ ) _n -C _{3 -6} cycloalkyl, and -(CH ₂ ) _n -4- to 6-membered heterocycle;

R ⁹ is H or C _1-6 alkyl;

R ¹⁰ is independently C _1-6 alkyl (optionally substituted with R ¹¹ ), C _2-6 alkenyl, C _2-6 alkynyl, -(CH ₂ ) _n -C _3-6 cycloalkyl, -O- 4- to 10-membered heterocycle (optionally substituted with R ¹¹ ), F, Cl, Br, CN, NO ₂ , =O, CO ₂ H, -(CH ₂ ) _n -OC _1-5 alkyl, -( CH ₂ ) _n -OR ¹¹ , and -(CH ₂ ) _n -NR ¹¹ R ¹¹ ;

R ¹¹ at each occurrence is independently selected from H, C _1-5 alkyl, -(CH ₂ ) _n -OH, C _3-6 cycloalkyl, and phenyl, or R ¹¹ and R ¹¹ are both attached. Together with the nitrogen atom to which it is located, it forms a heterocyclic ring optionally substituted with C _1-4 alkyl;

R ¹² is C _1-6 alkyl optionally substituted with R ¹¹ ;

n is, in each case, an integer independently selected from 0, 1, 2, 3, and 4;

p is, in each case, an integer independently selected from 0, 1, and 2.

In another aspect, the present invention

Ring A is independently

is selected from;

이고;Ring B is

ego;

---- is an arbitrary combination;

G ¹ independently

is selected from;

Y is -C(O)NH-;

R ¹ and R ² are independently selected from H and C _1-4 alkyl;

R ³ is independently selected from H, F, C _1-4 alkyl, haloalkyl, and -NHC(O)OC _1-4 alkyl; However, only one R ³ is present on the ring,

R ⁴ is independently selected from H, and C _1-4 alkyl;

R ⁷ is H

Provided are compounds of Formula II, or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

In another aspect, the invention provides a compound of Formula (IIa) or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

<Formula IIa>

In the above equation

Ring A is independently selected from 6-membered aryl and 5- to 6-membered heterocyclyl;

Ring B is a 5- to 10-membered heterocyclyl or a 5- to 10-membered heterocyclyl comprising a carbon atom and 1-4 heteroatoms selected from N, NR ^3c , O, and S(O) _p ; ;

G ¹ is independently selected from C _3-6 carbocyclyl and 5- to 10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl are substituted with 1-4 R ⁸ ;

W is independently selected from (CR ¹ R ² ) _1-2 , O, NH, and N(C _1-4 alkyl);

Y is independently selected from -CR ¹³ NH-, -NHC(=O)- and -C(=O)NH-;

R ¹ and R ² are independently H, D, halogen, haloalkyl, C _1-4 alkyl (optionally substituted with R ⁶ ), hydroxyl, and alkoxy (optionally substituted with R ⁶ ), and R ⁶ is selected from substituted C _3-5 cycloalkyl;

R ³ is independently H, halogen, C _1-4 alkyl (optionally substituted with R ⁶ ), CN, -(CH ₂ ) _n -OR ⁵ , -(CH ₂ ) _n -NR ⁵ R ⁵ , -(CH ₂ ) _n -C(=O)R ⁵ , and -(CH ₂ ) _n -C(=O)OR ⁵ ;

R ^3c is independently H, haloalkyl, C _1-4 alkyl (optionally substituted with R ⁶ ), -(CH ₂ ) _1-2 -OH, C(=O)C _1-4 alkyl, -(CH ₂ ) _1-2 -C(=O)OH, -C(=O)OC _1-4 alkyl, S(=O) _p C _1-6 alkyl, -(CH ₂ ) _n -C _3-10 carbocyclyl and -(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein the carbocyclyl and heterocyclyl are optionally substituted with R ⁶ ;

R ⁴ is independently H, OH, halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, -C(=O)NH ₂ , -C(=O)NH(C _1-4 alkyl), -C(=O)N(C _1-4 alkyl) ₂ , C _3-6 cycloalkyl, aryl, and 5- to 6-membered heterocyclyl, wherein the cycloalkyl, Aryl and heterocyclyl are optionally substituted with R ⁶ ;

R ⁵ is independently H, C _1-4 alkyl (optionally substituted with halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino, substituted amino), C _3-10 carbocyclyl and 4- to 10- is selected from the group heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with R ⁶ ;

R ⁶ is independently H, OH, =O, -(CH ₂ ) _n NH ₂ , -(CH ₂ ) _n CN, halogen, C _1-6 alkyl, -(CH ₂ ) _n -C(=O)OH , -(CH ₂ ) _n -C(=O)OC _1-4 alkyl, -(CH ₂ ) _n -OC _1-4 alkyl, -(CH ₂ ) _n -C(=O)NH ₂ , -(CH ₂ ) _n -C _3-10 carbocyclyl, -(CH ₂ ) _n -4- to 10-membered heterocyclyl, and -(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein the carbocyclyl and heterocyclyl are optionally substituted with R ¹⁰ ;

R ⁷ is independently selected from H, hydroxyl, halogen, C _1-2 haloalkyl, and C _1-2 alkyl;

R ⁸ is independently H, halogen, CN, NH ₂ , C _1-6 alkyl, haloalkyl, haloalkylcarbonylamino, arylamino, heteroarylamino, hydroxycarbonyl, haloalkylaminocarbonyl, arylalkylcar Bornyl, alkylcarbonyl, alkoxy, haloalkoxy, -(CH ₂ ) _n -aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl, and -(CH ₂ ) _n -4- to 12-membered heterocycle. selected from ryl, wherein said aryl, cycloalkyl, and heterocyclyl are optionally substituted with R ¹⁰ ;

Alternatively, two adjacent R ⁸ groups and G ¹ are

forming a fused heterocyclic group selected from;

R ⁹ is H or C _1-6 alkyl;

R ¹⁰ is independently H, C _1-6 alkyl (optionally substituted with R ¹¹ ), C _2-6 alkenyl, C _2-6 alkynyl, aryl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -O-4- to 10-membered heterocyclyl (optionally substituted with R ¹¹ ), F, Cl, Br, -(CH ₂ ) _n CN, NO ₂ , =O, C(=O)NR ¹² R ¹² , -(CH ₂ ) _n C(=O)OR ¹² , Si(C _1-4 alkyl) ₃ , -( CH ₂ ) _n -OR ¹² , -(CH ₂ ) _n -NR ¹² R ¹² , and -S(=O) _p C _1-6 alkyl, NR ¹² S(=O) _p C _1-6 alkyl, and S (=O) _p is selected from NR ¹² R ¹² ;

R ^10' is independently H, C _1-6 alkyl (optionally substituted with R ¹¹ ), aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), and -(CH ₂ ) _n -O-4- to 10-membered heterocyclyl (optionally substituted with R ¹¹ );

R ¹¹ at each occurrence is independently selected from H, halogen, C _1-5 alkyl, -(CH ₂ ) _n -OH, C _3-6 cycloalkyl, and phenyl;

R ¹² at each occurrence is independently selected from H, C _1-5 alkyl optionally substituted with R ¹¹ , C _3-6 cycloalkyl, phenyl, and heterocyclyl, or R ¹² and R ¹² are both together with the nitrogen atom to which it is attached forms a heterocyclic ring optionally substituted with C _1-4 alkyl;

R ¹³ is independently, at each occurrence, H, CF ₃ , C(=O)OH, C(=O)O(C _1-4 alkyl), and -C(=O)NH ₂ (C _1-4 alkoxy ) is selected from;

n is, in each case, an integer independently selected from 0, 1, 2, 3, and 4;

p is, in each case, an integer independently selected from 0, 1, and 2.

In another aspect, the invention provides a compound of Formula IIb or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

<Formula IIb>

In the above equation

Ring A is independently selected from phenyl and 5- to 6-membered heterocyclyl;

Ring B is a 5- to 10-membered heterocyclyl or a 5- to 6-membered heterocyclyl comprising a carbon atom and 1-4 heteroatoms selected from N, NR ^3c , O, and S(O) _p ; ;

W is independently selected from (CR ¹ R ² ) _1-2 , O, NH, and N(C _1-4 alkyl);

Y is independently selected from -CH ₂ NH-, -NHC(=O)- and -C(=O)NH-;

G ³ is independently selected from N and CR ^8a ;

G ⁴ is independently selected from N and CR ^8e ;

R ¹ and R ² are independently selected from H, D, halogen, CF ₃ , C _1-6 alkyl, and hydroxyl;

R ³ is independently H, halogen, C _1-4 alkyl (optionally substituted with R ⁶ ), CN, -(CH ₂ ) _n -OR ⁵ , -(CH ₂ ) _n -NR ⁵ R ⁵ , -(CH ₂ ) _n -C(=O)R ⁵ , and -(CH ₂ ) _n -C(=O)OR ⁵ ;

R ^3c is independently H, haloalkyl, C _1-4 alkyl (optionally substituted with R ⁶ ), -(CH ₂ ) _1-2 -OH, C(=O)C _1-4 alkyl, -(CH ₂ ) _1-2 -C(=O)OH, -C(=O)OC _1-4 alkyl, S(=O) _p C _1-6 alkyl, -(CH ₂ ) _n -C _3-10 carbocyclyl and -(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein the carbocyclyl and heterocyclyl are optionally substituted with R ⁶ ;

R ⁴ is independently H, OH, F, Cl, Br, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ , CN, C(=O)NH ₂ , C _3-6 cycloalkyl, aryl, and is selected from 5- to 6-membered heterocyclyl, wherein said cycloalkyl, aryl and heterocyclyl are optionally substituted with R ⁶ ;

R ⁵ is independently selected from H, and C _1-4 alkyl optionally substituted with halogen and hydroxyl;

R ⁶ is independently H, -(CH ₂ ) _n -OH, =O, NH ₂ , -(CH ₂ ) _n -CN, halogen, C _1-6 alkyl, -(CH ₂ ) _n -C(=O )OH, -(CH ₂ ) _n -C(=O)OC _1-4 alkyl, -(CH ₂ ) _n -OC _1-4 alkyl, -(CH ₂ ) _n -C _3-6 cycloalkyl, -( CH ₂ ) _n -4- to 10-membered heterocyclyl, and -O-(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are R ¹⁰ optionally substituted;

R ⁷ is independently selected from H, F, Cl, Br, CF ₃ , and CH ₃ ;

R ^8a is independently H, F, Cl, Br, I, -(CH ₂ ) _n CN, -(CH ₂ ) _n NH ₂ , C _1-2 alkyl, C _1-2 haloalkyl, OH, OC _{1- 2} alkyl, OC _1-2 haloalkyl, C(=O)OH, C(=O)OC _1-3 alkyl, C(=O)NH ₂ , C(=O)NHC _1-2 haloalkyl, C( =O)NHarylalkyl, C(=O)C _1-3 alkyl, NHC(=O)OC _1-2 alkyl, NHC(=O)C _1-2 haloalkyl, NH-aryl, NH-heteroaryl, is selected from aryl, C _3-6 cycloalkyl, and 4- to 12-membered heterocyclyl, wherein said aryl, cycloalkyl, and heterocyclyl are optionally substituted with R ¹⁰ ;

R ^8b is independently selected from H and F;

R ^8c is independently selected from H, F, Cl, methyl, ethyl, isopropyl, OCHF ₂ , and OCH ₃ ;

R ^8d is independently selected from H, F, and Cl;

R ^8e is independently selected from H, F, and Cl;

R ¹⁰ is independently H, C _1-6 alkyl (optionally substituted with R ¹¹ ), C _2-6 alkenyl, C _2-6 alkynyl, aryl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -O-4- to 10-membered heterocyclyl (optionally substituted with R ¹¹ ), F, Cl, Br, CN, NO ₂ , =O, CONR ¹² R ¹² , -(CH ₂ ) _n C(=O)OR ¹² , Si(C _1-4 alkyl) ₃ , -(CH ₂ ) _n -OR ¹² , and -( CH ₂ ) _n -NR ¹² R ¹² , -S(=O) _p C _1-6 alkyl, NR ¹² S(=O) _p C _1-6 alkyl, and S(=O) _p NR ¹² R ¹² become;

R ¹¹ at each occurrence is independently selected from H, halogen, C _1-5 alkyl, -(CH ₂ ) _n -OH, C _3-6 cycloalkyl, and phenyl;

R ¹² at each occurrence is independently selected from H, C _1-5 alkyl optionally substituted with R ¹¹ , C _3-6 cycloalkyl, phenyl, and heterocyclyl, or R ¹² and R ¹² are both together with the nitrogen atom to which it is attached forms a heterocyclic ring optionally substituted with C _1-4 alkyl;

n is, in each case, an integer independently selected from 0, 1, and 2;

p is, in each case, an integer independently selected from 0, 1, and 2.

In another aspect, the present invention

Ring A is independently selected from phenyl and 5- to 6-membered heterocyclyl;

Ring B is a 5- to 6-membered heteroaryl comprising a carbon atom and 1-4 heteroatoms selected from N and NR ^3c ;

W is independently selected from (CR ¹ R ² ) _1-2 , O, NH, and N(C _1-4 alkyl);

Y is independently selected from -CH ₂ NH-, -NHC(=O)- and -C(=O)NH-;

G ³ is CR ^8a ;

G ⁴ is CR ^8e ;

R ¹ and R ² are independently selected from H, D, halogen, CF ₃ , C _1-6 alkyl, and hydroxyl;

R ³ is independently H, halogen, C _1-4 alkyl (optionally substituted with R ⁶ ), CN, -(CH ₂ ) _n -OR ⁵ , -(CH ₂ ) _n -C(=O)R ⁵ , and -(CH ₂ ) _n -C(=O)OR ⁵ ;

R ^3c is independently H, haloalkyl, C _1-4 alkyl (optionally substituted with R ⁶ ), -(CH ₂ ) _1-2 -OH, C(=O)C _1-4 alkyl, -(CH ₂ ) _1-2 -C(=O)OH, -C(=O)OC _1-4 alkyl, S(=O) _p C _1-6 alkyl, -(CH ₂ ) _n -C _3-10 carbocyclyl and -(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein the carbocyclyl and heterocyclyl are optionally substituted with R ⁶ ;

R ⁴ is independently H, OH, F, Cl, Br, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ , CN, C(=O)NH ₂ , C _3-6 cycloalkyl, aryl, and is selected from 5- to 6-membered heterocyclyl, wherein said cycloalkyl, aryl and heterocyclyl are optionally substituted with R ⁶ ;

R ⁵ is independently selected from H and C _1-4 alkyl;

R ⁶ is independently H, -(CH ₂ ) _n -OH, =O, NH ₂ , -(CH ₂ ) _n -CN, halogen, C _1-6 alkyl, -(CH ₂ ) _n -C(=O )OH, -(CH ₂ ) _n -C(=O)OC _1-4 alkyl, -(CH ₂ ) _n -OC _1-4 alkyl, -(CH ₂ ) _n -C _3-6 cycloalkyl, -( CH ₂ ) _n -4- to 10-membered heterocyclyl, and -O-(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are R ¹⁰ optionally substituted;

R ⁷ is independently selected from H, F, Cl, Br, and methyl;

R ^8a is independently H, F, Cl, Br, I, -(CH ₂ ) _n CN, -(CH ₂ ) _n NH ₂ , CH ₃ CHF ₂ , CCH ₃ F ₂ , CF ₃ , OH, OCH ₃ , OCF ₃ , OCHF ₂ , C(=O)CH ₃ , C(=O)OH, C(=O)OCH ₃ , C(=O)NH ₂ , C(=O)NHCH ₂ CF ₃ , C(= O)NHCH ₂ Ph, NHC(=O)OCH ₃ , NHC(=O)CF ₃ ,

is selected from;

R ^8b is independently selected from H and F;

R ^8c is independently selected from H, F, Cl, methyl, ethyl, isopropyl, and OCH ₃ ;

R ^8d is independently selected from H, F, and Cl;

R ^8e is independently selected from H, F, and Cl;

R ¹⁰ is independently H, C _1-6 alkyl (optionally substituted with R ¹¹ ), C _2-6 alkenyl, C _2-6 alkynyl, aryl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -O-4- to 10-membered heterocyclyl (optionally substituted with R ¹¹ ), F, Cl, Br, CN, NO ₂ , =O, CONR ¹² R ¹² , -(CH ₂ ) _n -C(=O)OR ¹² , Si(C _1-4 alkyl) ₃ , -(CH ₂ ) _n -OR ¹² , -( CH ₂ ) _n -NR ¹² R ¹² , -S(=O) _p C _1-6 alkyl, NR ¹² S(=O) _p C _1-6 alkyl, and S(=O) _p NR ¹² R ¹² become;

R ^10' is independently H, C _1-6 alkyl (optionally substituted with R ¹¹ ), aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), and -(CH ₂ ) _n -O-4- to 10-membered heterocyclyl (optionally substituted with R ¹¹ );

R ¹¹ at each occurrence is independently selected from H, halogen, C _1-5 alkyl, -(CH ₂ ) _n -OH, C _3-6 cycloalkyl, and phenyl;

R ¹² at _{each occurrence is independently selected from H, C 1-5} ^alkyl , C _3-6 cycloalkyl, phenyl and heterocyclyl optionally substituted with R 11 , or R ¹² and R ¹² are both attached. Together with the nitrogen atom to which it is located, it forms a heterocyclic ring optionally substituted with C _1-4 alkyl;

n is, in each instance, an integer independently selected from 0, 1, and 2;

where p is, in each case, an integer independently selected from 0, 1, and 2.

Provided are compounds of Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

In another aspect, the invention provides a compound of Formula IIc or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

<Formula IIc>

In the above equation

Ring A is independently selected from phenyl and 5- to 6-membered heterocyclyl;

Ring B is a 5- to 6-membered heteroaryl comprising a carbon atom and 1-3 heteroatoms selected from N and NR ^3c ;

W is independently selected from (CR ¹ R ² ) _1-2 , O, NH, and N(C _1-4 alkyl);

Y is independently selected from -CH ₂ NH-, -NHC(=O)- and -C(=O)NH-;

R ¹ and R ² are independently selected from H, D, F, C _1-4 alkyl, and hydroxyl;

R ³ is independently selected from H, halogen, haloalkyl, C _1-4 alkyl (optionally substituted with R ⁶ ), and CN;

R ^3c is independently H, haloalkyl, C _1-4 alkyl (optionally substituted with R ⁶ ), -(CH ₂ ) _1-2 -OH, C(=O)C _1-4 alkyl, -(CH ₂ ) _1-2 -C(=O)OH, -C(=O)OC _1-4 alkyl, S(=O) _p C _1-6 alkyl, -(CH ₂ ) _n -C _3-10 carbocyclyl and -(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein the carbocyclyl and heterocyclyl are optionally substituted with R ⁶ ;

R ⁴ is independently H, OH, F, Cl, Br, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ , CN; selected from C(=O)NH ₂ , C _3-6 cycloalkyl, aryl, and 5- to 6-membered heterocyclyl;

R ⁶ is independently H, -(CH ₂ ) _n -OH, =O, NH ₂ , -(CH ₂ ) _n -CN, halogen, C _1-6 alkyl, -(CH ₂ ) _n -C(=O )OH, -(CH ₂ ) _n -C(=O)OC _1-4 alkyl, -(CH ₂ ) _n -OC _1-4 alkyl, -(CH ₂ ) _n -C _3-6 cycloalkyl, -( CH ₂ ) _n -4- to 10-membered heterocyclyl, and -O-(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are R ¹⁰ optionally substituted;

R ^8b is independently selected from H and F;

R ^8c is independently selected from H, F, Cl, CH ₃ , and OCH ₃ ;

R ¹⁰ is independently H, C _1-6 alkyl (optionally substituted with R ¹¹ ), C _2-6 alkenyl, C _2-6 alkynyl, aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -O-4- to 10-membered heterocyclyl (optionally substituted with R ¹¹ ), F, Cl, Br, CN, NO ₂ , =O, C(=O)NR ¹² R ¹² , C(=O)OR ¹² , Si(C _1-4 alkyl) ₃ , -(CH ₂ ) _n -OR ¹² , -(CH ₂ ) _n -NR ¹² R ¹² , -S(=O) _p C _1-6 alkyl, NR ¹² S(=O) _p C _1-6 alkyl, and S(=O) _p NR ¹² R ¹² ;

R ¹¹ at each occurrence is independently selected from H, halogen, C _1-5 alkyl, -(CH ₂ ) _n -OH, C _3-6 cycloalkyl, and phenyl;

R ¹² at each occurrence is independently selected from H, C _1-5 alkyl, C _3-6 cycloalkyl, phenyl, and heterocyclyl, or R ¹² and R ¹² are the nitrogen atom to which they are both attached. together form a heterocyclic ring optionally substituted with C _1-4 alkyl;

n is, in each case, an integer independently selected from 0, 1, and 2;

p is, in each case, an integer independently selected from 0, 1, and 2.

In another aspect, the invention provides a compound of Formula IId or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

<Formula IId>

In the above equation

---- is an arbitrary combination;

Ring A is independently selected from phenyl and 5- to 6-membered heterocyclyl;

W is independently selected from CHR ^1a , O, NH, and N(C _1-4 alkyl);

G ⁵ is independently selected from CH ₂ and NR ^3c ;

G ⁶ is independently selected from CH ₂ and NR ^3c ;

provided that when G ⁵ is CH ₂ , G ⁶ is NR ^3c ; When G ⁵ is NR ^3c , G ⁶ is CH ₂ and only one R ^3c is present on the ring;

Y is independently selected from -NHC(=O)- and -C(=O)NH-;

R ¹ is independently selected from H and C _1-4 alkyl;

R ^1a is independently selected from H, D, F, CH ₃ , and OH;

R ² is independently selected from H, D, and OH;

R ^3c is independently H, haloalkyl, C _1-4 alkyl (optionally substituted with R ⁶ ), -(CH ₂ ) _1-2 -OH, C(=O)C _1-4 alkyl, -(CH ₂ ) _1-2 -C(=O)OH, -C(=O)OC _1-4 alkyl, S(=O) _p C _1-6 alkyl, phenyl optionally substituted with R ⁶ , optionally substituted with R ⁶ is selected from 5- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl optionally substituted with R ⁶ ;

R ⁴ is independently selected from H, OH, F, Cl, Br, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ , CN, and C(=O)NH ₂ ;

R ⁶ is independently H, -(CH ₂ ) _n -OH, =O, NH ₂ , -(CH ₂ ) _n -CN, halogen, C _1-6 alkyl, -(CH ₂ ) _n -C(=O )OH, -(CH ₂ ) _n -C(=O)OC _1-4 alkyl, -(CH ₂ ) _n -OC _1-4 alkyl, -(CH ₂ ) _n -C _3-6 cycloalkyl, -( CH ₂ ) _n -4- to 10-membered heterocyclyl, and -O-(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are R ¹⁰ optionally substituted;

R ^8b is independently selected from H and F;

R ^8c is independently selected from H, F, Cl, CH ₃ , and OCH ₃ ;

R ¹⁰ is independently H, C _1-6 alkyl (optionally substituted with R ¹¹ ), aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -O-4- to 10-membered heterocyclyl (optionally substituted with R ¹¹ ), F, Cl, Br, CN, NO ₂ , =O, C(=O)NR ¹² R ¹² , C(=O )OR ¹² , Si(C _1-4 alkyl) ₃ , -(CH ₂ ) _n -OR ¹² , and -(CH ₂ ) _n -NR ¹² R ¹² , -S(=O) _p C _1-6 alkyl, NR ¹² S(=O) _p C _1-6 alkyl, and S(=O) _p NR ¹² R ¹² ;

R ¹¹ at each occurrence is independently selected from H, halogen, C _1-5 alkyl, -(CH ₂ ) _n -OH, C _3-6 cycloalkyl, and phenyl;

R ¹² at each occurrence is independently selected from H, C _1-5 alkyl, C _3-6 cycloalkyl, phenyl, and heterocyclyl, or R ¹² and R ¹² are the nitrogen atom to which they are both attached. together form a heterocyclic ring optionally substituted with C _1-4 alkyl;

n is, in each case, an integer independently selected from 0, 1, and 2;

p is, in each case, an integer independently selected from 0, 1, and 2.

In another aspect, the invention provides a compound of Formula IIe or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

<Formula IIe>

In the above equation

Ring A is independently

is selected from;

R ¹ is independently selected from H and C _1-4 alkyl;

R ^1a is independently selected from H, D, F, CH ₃ , and OH;

R ² is independently selected from H, D, and OH;

R ^3c is independently H, CHF ₂ , CD ₃ , CH ₃ , CH ₂ CH ₂ OH, CH ₂ C(=O)OH, SO ₂ CH ₃ , phenyl optionally substituted with R ⁶ , and optionally substituted with R ⁶ is selected from 5- to 6-membered heteroaryl;

R ⁴ is independently selected from H, F, and C(=O)NH ₂ ;

R ⁶ is independently H, -(CH ₂ ) _n -OH, =O, NH ₂ , -(CH ₂ ) _n -CN, halogen, C _1-6 alkyl, -(CH ₂ ) _n -C(=O )OH, -(CH ₂ ) _n -C(=O)OC _1-4 alkyl, -(CH ₂ ) _n -OC _1-4 alkyl, -(CH ₂ ) _n -C _3-6 cycloalkyl, -( CH ₂ ) _n -4- to 10-membered heterocyclyl, and -O-(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are R ¹⁰ optionally substituted;

R ^8b is independently selected from H and F;

R ^8c is independently selected from H, F, Cl, CH ₃ , and OCH ₃ ;

R ¹⁰ is independently H, CF ₃ , CHF ₂ , CH ₂ F, aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), heteroaryl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -O-4- to 10-membered heterocyclyl (optionally substituted with R ¹¹ ), F, Cl, Br, CN, NO ₂ , =O, C(=O)NR ¹² R ¹² , -(CH ₂ ) _n -C(=O)OR ¹² , Si(C _1-4 alkyl) ₃ , -(CH ₂ ) _n -OR ¹² , -(CH ₂ ) _n -NR ¹² R ¹² , -S(=O) _p C _1-6 alkyl, NR ¹² S(=O) _p C _1-6 alkyl, and S(=O) _p NR ¹² R ¹² ;

R ¹¹ at each occurrence is independently selected from H, halogen, C _1-5 alkyl, -(CH ₂ ) _n -OH, C _3-6 cycloalkyl, and phenyl;

R ¹² at each occurrence is independently selected from H, C _1-5 alkyl, C _3-6 cycloalkyl, phenyl, and heterocyclyl, or R ¹² and R ¹² are the nitrogen atom to which they are both attached. together form a heterocyclic ring optionally substituted with C _1-4 alkyl;

n is, in each case, an integer independently selected from 0, 1, and 2.

In another aspect, the invention provides a compound of Formula (IIf) or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

<Formula IIf>

In the above equation

Ring A is independently

is selected from;

R ¹ is independently selected from H and C _1-4 alkyl;

R ^1a is independently selected from H, D, F, CH ₃ , and OH;

R ² is independently selected from H, D, and OH;

R ^3c is independently H, CHF ₂ , CD ₃ , CH ₃ , SO ₂ CH ₃ , phenyl optionally substituted with R ⁶ , and 5- to ⁶ -membered heterocyclyl optionally substituted with R ⁶ is selected from substituted 5- to 6-membered heteroaryl;

R ⁴ is independently selected from H and F;

R ⁶ is independently OH, =O, NH ₂ , CN, halogen, C _1-6 alkyl, -(CH ₂ ) _n -C _3-6 cycloalkyl, -(CH ₂ ) _n -4- to 10-membered heterocyclyl, and -O-(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with R ¹⁰ ;

R ^8b is independently selected from H and F;

R ^8c is independently selected from H, F, Cl, CH ₃ , and OCH ₃ ;

R ¹⁰ is independently H, CF ₃ , CHF ₂ , C(CH ₃ ) ₂ OH, aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -O-4- to 10-membered heterocyclyl (optionally substituted with R ¹¹ ), F, Cl, Br, CN, NO ₂ , =O, C(=O)NR ¹² R ¹² , C(=O )OR ¹² , Si(C _1-4 alkyl) ₃ , -(CH ₂ ) _n -OR ¹² , -(CH ₂ ) _n -NR ¹² R ¹² , -S(=O) _p C _1-6 alkyl, NR ¹² S(=O) _p C _1-6 alkyl, and S(=O) _p NR ¹² R ¹² ;

R ¹¹ at each occurrence is independently selected from H, halogen, C _1-5 alkyl, -(CH ₂ ) _n -OH, C _3-6 cycloalkyl, and phenyl;

R ¹² at each occurrence is independently selected from H, C _1-5 alkyl, C _3-6 cycloalkyl, phenyl, and heterocyclyl, or R ¹² and R ¹² are the nitrogen atom to which they are both attached. together form a heterocyclic ring optionally substituted with C _1-4 alkyl;

n is, in each case, an integer independently selected from 0, 1, and 2.

In another aspect, the present invention

Ring A is independently

is selected from;

R ¹ is independently selected from H and C _1-4 alkyl;

R ^1a is independently selected from H, D, F, CH ₃ , and OH;

R ² is independently selected from H, D, and OH;

R ^3c is independently optionally substituted with H, CHF ₂ , CD ₃ , CH ₃ , SO ₂ CH ₃ , R ⁶ , and

is selected from heterocyclyl selected from;

R ⁴ is independently selected from H and F;

R ⁶ is independently selected from H, OH, OC _1-4 alkyl, CN, F, Cl, and C _1-4 alkyl;

R ^8b is independently selected from H and F;

R ^8c is independently selected from H, F, Cl, CH ₃ , and OCH ₃ ;

R ¹⁰ is independently H, CF ₃ , CHF ₂ , C(CH ₃ ) ₂ OH, aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -O-4- to 10-membered heterocyclyl (optionally substituted with R ¹¹ ), F, Cl, Br, CN, NO ₂ , =O, C(=O)NR ¹² R ¹² , C(=O )OR ¹² , Si(C _1-4 alkyl) ₃ , -(CH ₂ ) _n -OR ¹² , -(CH ₂ ) _n -NR ¹² R ¹² , -S(=O) _p C _1-6 alkyl, NR ¹² S(=O) _p C _1-6 alkyl, and S(=O) _p NR ¹² R ¹² ;

R ¹¹ at each occurrence is independently selected from H, halogen, C _1-5 alkyl, -(CH ₂ ) _n -OH, C _3-6 cycloalkyl, and phenyl;

R ¹² at each occurrence is independently selected from H, C _1-5 alkyl, C _3-6 cycloalkyl, phenyl, and heterocyclyl, or R ¹² and R ¹² are the nitrogen atom to which they are both attached. together form a heterocyclic ring optionally substituted with C _1-4 alkyl;

where n is, in each case, an integer independently selected from 0, 1, and 2.

Provided are compounds of Formula (IIf) or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

In another aspect, the invention provides a compound of Formula IIg or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

<Formula IIg>

In the above equation

Ring A is independently

is selected from;

R ¹ is independently selected from H and C _1-4 alkyl;

R ^1a is independently selected from H, F, CH ₃ , and OH;

R ² is independently selected from H and OH;

R ^3c is independently selected from H, CHF ₂ , CD ₃ , and CH ₃ ;

R ⁴ is independently selected from H and F;

R ^8b is independently selected from H and F;

R ^8c is independently selected from H, F, Cl, CH ₃ , and OCH ₃ ;

R ¹⁰ is independently H, CF ₃ , CHF ₂ , aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -O-4- to 10 -one heterocyclyl (optionally substituted with R ¹¹ ), F, Cl, Br, CN, NO ₂ , =O, C(=O)NR ¹² R ¹² , C(=O)OR ¹² , Si(C _{1 -4} alkyl) ₃ , -(CH ₂ ) _n -OR ¹² , -(CH ₂ ) _n -NR ¹² R ¹² , -S(=O) _p C _1-6 alkyl, NR ¹² S(=O) _p C _1-6 alkyl, and S(=O) _p NR ¹² R ¹² ;

R ¹¹ at each occurrence is independently selected from H, halogen, C _1-5 alkyl, -(CH ₂ ) _n -OH, C _3-6 cycloalkyl, and phenyl;

R ¹² at each occurrence is independently selected from H, C _1-5 alkyl, C _3-6 cycloalkyl, phenyl, and heterocyclyl, or R ¹² and R ¹² are the nitrogen atom to which they are both attached. together form a heterocyclic ring optionally substituted with C _1-4 alkyl;

n is, in each case, an integer independently selected from 0, 1, and 2.

In another aspect, the invention provides a compound of Formula (IIIa) or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

<Formula IIIa>

In the above equation

Ring A is independently selected from phenyl and 5- to 6-membered heterocycle;

G ¹ is independently selected from aryl, C _3-6 cycloalkyl and 5- to 6-membered heterocycle, wherein said aryl, cycloalkyl and heterocycle are substituted with 1-4 R ⁸ ;

G ² is N;

R ¹ and R ² are independently selected from H, halogen, CF ₃ , C _1-6 alkyl, and hydroxyl;

R ³ is independently H, halogen, haloalkyl, C _1-4 alkyl (optionally substituted with R ⁶ ), C _2-4 alkenyl (optionally substituted with R ⁶ ), CN, NO ₂ , -(CH ₂ ) _n -OR ⁵ , -(CH ₂ ) _n -NR ⁵ R ⁵ , -(CH ₂ ) _n -C(=O)OR ⁵ , -(CH ₂ ) _n -NHC(=O)OR ⁵ , -( CH ₂ ) _n -NHC(=O)R ⁵ , -(CH ₂ ) _n -NHC(N-CN)NHR ⁵ , -(CH ₂ ) _n -NHC(NH)NHR ⁵ , -(CH ₂ ) _n - N=CHNR ⁵ R ⁵ , -(CH ₂ ) _n -NHC(=O)NR ⁵ R ⁵ , -(CH ₂ ) _n -C(=O)NR ⁵ R ⁵ , -(CH ₂ ) _n -NHC( S)NR ⁹ C(=O)R ⁵ , -(CH ₂ ) _n -S(=O) _p C _1-6 alkyl, optionally substituted with R ¹¹ , -(CH ₂ ) _n -S(=O) _p NR ⁵ R ⁵ , -(CH ₂ ) _n -NHS(=O) _p NR ⁵ R ⁵ , -(CH ₂ ) _n -NHS(=O) _p C _1-6 alkyl, -(, optionally substituted with R ¹¹ CH ₂ ) _n -C _3-10 carbocycle and -(CH ₂ ) _n -4- to 10-membered heterocycle, wherein said carbocycle and heterocycle are optionally substituted with R ⁶ ; Optionally, two adjacent R ³ groups on the carbocycle and heterocycle may form a ring optionally substituted with R ⁶ ;

R ^3a is independently selected from H and halogen;

R ^3b is independently selected from H, halogen, methyl, and CN;

R ⁴ is independently H, OH, F, Cl, Br, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ , CN, C _3-6 cycloalkyl, aryl, and 5- to 6-membered heterocycle selected from wherein the cycloalkyl, aryl and heterocycle are optionally substituted with R ⁶ ;

R ⁵ is independently H, C _1-4 alkyl (optionally substituted with halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino, substituted amino), -(CH ₂ ) _n -C _3-10 carbo cycle and -(CH ₂ ) _n -4- to 10-membered heterocycle, wherein the carbocycle and heterocycle are optionally substituted with R ⁶ ;

R ⁶ is independently -(CH ₂ ) _n -OH, =O, NH ₂ , -(CH ₂ ) _n -CN, halogen, C _1-6 alkyl, -(CH ₂ ) _n -C(=O)OH , -(CH ₂ ) _n -C(=O)OC _1-4 alkyl, -(CH ₂ ) _n -OC _1-4 alkyl, -(CH ₂ ) _n -C _3-6 cycloalkyl, -(CH ₂ ) _n -4- to 10-membered heterocycle, and -O-(CH ₂ ) _n -4- to 10-membered heterocycle, wherein the cycloalkyl and heterocycle are optionally substituted with R ¹⁰ ;

R ⁷ is independently selected from H, F, Cl, and methyl;

R ⁸ is independently H, halogen, CN, NH ₂ , C _1-6 alkyl, haloalkyl, alkylcarbonyl, alkoxy, haloalkoxy, aryl, C _3-6 cycloalkyl, and 4- to 6-membered heterocycle selected from wherein the aryl, cycloalkyl, and heterocycle are optionally substituted with R ¹⁰ ;

R ¹⁰ is independently H, C _1-6 alkyl (optionally substituted with R ¹¹ ), C _2-6 alkenyl, C _2-6 alkynyl, aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -O-4- to 10-membered heterocycle (optionally substituted with R ¹¹ ), F, Cl, Br, CN, NO ₂ , =O, C (=O)NR ¹² R ¹² , C(=O)OR ¹² , Si(C _1-4 alkyl) ₃ , -(CH ₂ ) _n -OR ¹² , and -(CH ₂ ) _n -NR ¹² R ¹² being selected;

R ¹¹ at each occurrence is independently selected from H, halogen, C _1-5 alkyl, -(CH ₂ ) _n -OH, C _3-6 cycloalkyl, and phenyl;

R ¹² at each occurrence is independently selected from H, C _1-5 alkyl, C _3-6 cycloalkyl, phenyl, and heterocycle, or R ¹² and R ¹² together with the nitrogen atom to which they are both attached forming a heterocyclic ring optionally substituted with C _1-4 alkyl;

n is, in each case, an integer independently selected from 0, 1, and 2;

p is, in each case, an integer independently selected from 0, 1, and 2.

In another aspect, the invention provides a compound of Formula IIIb or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

<Formula IIIb>

In the above equation

Ring A is independently selected from phenyl and 5- to 6-membered heterocyclyl;

G ¹ is independently selected from aryl, C _3-6 cycloalkyl and 5- to 6-membered heterocyclyl, wherein said aryl, cycloalkyl and heterocyclyl are substituted with 1-4 R ⁸ ;

G ² is independently selected from N and CR ^3b ;

G ⁷ is independently selected from N and CR ³ ;

G ⁸ is independently selected from N and CR ³ ;

provided that at least one of G ² , G ⁶ , and G ⁷ is N;

R ¹ and R ² are independently selected from H, halogen, CF ₃ , C _1-6 alkyl, and hydroxyl;

R ³ is independently H, halogen, haloalkyl, C _1-4 alkyl (optionally substituted with R ⁶ ), C _2-4 alkenyl (optionally substituted with R ⁶ ), CN, NO ₂ , -(CH ₂ ) _n -OR ⁵ , -(CH ₂ ) _n -NR ⁵ R ⁵ , -(CH ₂ ) _n -C(=O)OR ⁵ , -(CH ₂ ) _n -NHC(=O)OR ⁵ , -( CH ₂ ) _n -NHC(=O)R ⁵ , -(CH ₂ ) _n -NHC(N-CN)NHR ⁵ , -(CH ₂ ) _n -NHC(NH)NHR ⁵ , -(CH ₂ ) _n - N=CHNR ⁵ R ⁵ , -(CH ₂ ) _n -NHC(=O)NR ⁵ R ⁵ , -(CH ₂ ) _n -C(=O)NR ⁵ R ⁵ , -(CH ₂ ) _n -NHC( S)NR ⁹ C(=O)R ⁵ , -(CH ₂ ) _n -S(=O) _p C _1-6 alkyl, optionally substituted with R ¹¹ , -(CH ₂ ) _n -S(=O) _p NR ⁵ R ⁵ , -(CH ₂ ) _n -NHS(=O) _p NR ⁵ R ⁵ , -(CH ₂ ) _n -NHS(=O) _p C _1-6 alkyl, -(, optionally substituted with R ¹¹ CH ₂ ) _n -C _3-10 carbocyclyl and -(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with R ⁶ ; Optionally, two adjacent R ³ groups on carbocyclyl and heterocyclyl may form a ring optionally substituted with R ⁶ ;

R ^3a is independently selected from H and halogen;

R ^3b is independently selected from H, halogen, methyl, and CN;

R ⁴ is independently H, OH, F, Cl, Br, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ , CN, C _3-6 cycloalkyl, aryl, and 5- to 6-membered heterocycle selected from ryl, wherein said cycloalkyl, aryl and heterocyclyl are optionally substituted with R ⁶ ;

R ⁵ is independently H, C _1-4 alkyl (optionally substituted with halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino, substituted amino), -(CH ₂ ) _n -C _3-10 carboxy is selected from cryl and -(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with R ⁶ ;

R ⁶ is independently -(CH ₂ ) _n -OH, =O, NH ₂ , -(CH ₂ ) _n -CN, halogen, C _1-6 alkyl, -(CH ₂ ) _n -C(=O)OH , -(CH ₂ ) _n -C(=O)OC _1-4 alkyl, -(CH ₂ ) _n -OC _1-4 alkyl, -(CH ₂ ) _n -C _3-6 cycloalkyl, -(CH ₂ ) is selected from _n -4- to 10-membered heterocyclyl, and -O-(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted with R ¹⁰ become;

R ⁷ is independently selected from H, F, Cl, and methyl;

R ⁸ is independently H, halogen, CN, NH ₂ , C _1-6 alkyl, haloalkyl, alkylcarbonyl, alkoxy, haloalkoxy, aryl, C _3-6 cycloalkyl, and 4- to 12-membered heterocycle. selected from ryl, wherein said aryl, cycloalkyl, and heterocyclyl are optionally substituted with R ¹⁰ ;

R ¹⁰ is independently H, C _1-6 alkyl (optionally substituted with R ¹¹ ), C _2-6 alkenyl, C _2-6 alkynyl, aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -O-4- to 10-membered heterocyclyl (optionally substituted with R ¹¹ ), F, Cl, Br, CN, NO ₂ , =O, C(=O)NR ¹² R ¹² , C(=O)OR ¹² , Si(C _1-4 alkyl) ₃ , -(CH ₂ ) _n -OR ¹² , -(CH ₂ ) _n -NR ¹² R ¹² , -S(=O) _p C _1-6 alkyl, NR ¹² S(=O) _p C _1-6 alkyl, and S(=O) _p NR ¹² R ¹² ;

R ¹¹ at each occurrence is independently selected from H, halogen, C _1-5 alkyl, -(CH ₂ ) _n -OH, C _3-6 cycloalkyl, and phenyl;

R ¹² at each occurrence is independently selected from H, C _1-5 alkyl, C _3-6 cycloalkyl, phenyl, and heterocyclyl, or R ¹² and R ¹² are the nitrogen atom to which they are both attached. together form a heterocyclic ring optionally substituted with C _1-4 alkyl;

n is, in each case, an integer independently selected from 0, 1, and 2;

p is, in each case, an integer independently selected from 0, 1, and 2.

In another aspect, the invention provides a compound of Formula IVb or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

<Formula IVb>

In the above equation

Ring A is independently

is selected from;

R ¹ and R ² are independently selected from H, F, C _1-4 alkyl, and OH;

R ^1a at each occurrence is independently selected from H, F, CH ₃ , and OH;

R ³ is independently selected from H, F, Cl, Br, I, C _2-4 alkenyl (optionally substituted C(=O)OH), CN, and -(CH ₂ ) _n -OH;

R ⁴ is independently selected from H, OH, F, OC _1-4 alkyl, C _1-4 alkyl, CN, C _3-6 cycloalkyl, aryl, and 5- to 6-membered heterocyclyl, wherein cycloalkyl, aryl and heterocyclyl are optionally substituted with R ⁶ ;

R ⁶ is independently OH, NH ₂ , halogen, C _1-6 alkyl, C _3-6 cycloalkyl, -(CH ₂ ) _n -C(=O)OH, -(CH ₂ ) _n -C(=O )OC _1-4 alkyl, -(CH ₂ ) _n -OC _1-4 alkyl, =O, C _3-6 cycloalkyl, 4- to 10-membered heterocyclyl, and -O-4- to 10-membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with R ¹⁰ ;

R ^8a is independently H, F, Cl, Br, CN, OCH ₃ , OCF ₃ , CH ₃ , C(=O)CH ₃ , CF ₃ , OCHF ₂ , NHC(=O)C _1-4 alkyl, aryl , C _3-6 cycloalkyl, and 4- to 12-membered heterocyclyl, wherein the aryl, cycloalkyl, and heterocyclyl are optionally substituted with R ¹⁰ ;

R ^8b is independently selected from H and F;

R ^8c is independently selected from H, F, Cl, CH ₃ , and OCH ₃ ;

R ¹⁰ is independently selected from C _1-6 alkyl, -C _3-6 cycloalkyl, F, Cl, Br, CF ₃ , CHF ₂ , CN, and OC _1-5 alkyl;

n is, in each case, an integer independently selected from 0, 1, and 2.

In another aspect, the present invention

Ring A is independently

is selected from;

Ring B is independently

is selected from;

W is independently selected from CHR ^1a , O, NH, and N(C _1-4 alkyl);

R ¹ is independently selected from H and C _1-4 alkyl;

R ^1a is independently selected from HF, CH ₃ , and hydroxyl;

R ² is independently selected from H and hydroxyl;

R ³ is independently H, =O, F, CHF ₂ , CF ₃ , OCF ₃ , OCHF ₂ , CH ₃ , CN, -(CH ₂ ) _0-2 -OH, OC _1-4 alkyl, C(=O )C _1-4 alkyl, -(CH ₂ ) _0-1 -C(=O)OH, -C(=O)OC _1-4 alkyl, -S(=O) ₂ C _1-4 alkyl, and - NHC(=O)OC _1-4 alkyl;

R ^3c is independently selected from H, CF ₂ H, CF ₃ , C _1-4 alkyl, and CD ₃ ;

R ⁴ is independently selected from H and F;

R ^8b is independently selected from H and F;

R ^8c is independently selected from H and Cl;

R ¹⁰ is independently H, C _1-6 alkyl (optionally substituted with R ¹¹ ), aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -O-4- to 10-membered heterocyclyl, F, Cl, Br, CN, C(=O)NR ¹² R ¹² , Si(C _1-4 alkyl) ₃ , and -(CH ₂ ) _n - OR is selected from ¹² ;

R ¹¹ at each occurrence is independently selected from H, halogen, and C _1-5 alkyl;

n is, in each instance, an integer independently selected from 0, 1, 2, 3, and 4;

wherein the other variable is as defined in formula IVb above.

Provided are compounds of Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

In another aspect, the present invention

Ring A is independently

is selected from;

Ring B is independently

is selected from;

W is independently selected from CHR ^1a , O, NH, and N(C _1-4 alkyl);

R ¹ is independently selected from H and C _1-4 alkyl;

R ^1a is independently selected from HF, CH ₃ , and hydroxyl;

R ² is independently selected from H and hydroxyl;

R ³ is independently H, =O, F, CHF ₂ , CF ₃ , OCF ₃ , OCHF ₂ , CH ₃ , CN, -(CH ₂ ) _0-2 -OH, OC _1-4 alkyl, C(=O )C _1-4 alkyl, -(CH ₂ ) _0-1 -C(=O)OH, -C(=O)OC _1-4 alkyl, -S(=O) ₂ C _1-4 alkyl, and - NHC(=O)OC _1-4 alkyl;

R ^3c is independently selected from H, CF ₂ H, CF ₃ , C _1-4 alkyl, and CD ₃ ;

R ⁴ is independently selected from H and F;

R ^8b is independently selected from H and F;

R ^8c is independently selected from H and Cl;

R ¹⁰ is independently H, C _1-6 alkyl (optionally substituted with R ¹¹ ), aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -O-4- to 10-membered heterocyclyl, F, Cl, Br, CN, C(=O)NR ¹² R ¹² , Si(C _1-4 alkyl) ₃ , and -(CH ₂ ) _n - OR is selected from ¹² ;

R ¹¹ at each occurrence is independently selected from H, halogen, and C _1-5 alkyl;

n is, in each instance, an integer independently selected from 0, 1, 2, 3, and 4;

wherein the other variable is as defined in Formula IIc above.

Provided are compounds of Formula IIc, or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

In another aspect, the present invention

Ring A is independently

is selected from;

Ring B is independently

is selected from;

G ¹ independently

is selected from;

W is independently selected from CHR ¹ , O, NH, and N(C _1-4 alkyl);

Y is independently selected from -NH-, -NHC(=O)- and -C(=O)NH-;

R ¹ and R ² are independently selected from H, F, C _1-4 alkyl, and hydroxyl;

R ³ is independently H, =O, F, CHF ₂ , CF ₃ , OCF ₃ , OCHF ₂ , CH ₃ , CN, -(CH ₂ ) _0-2 -OH, OC _1-4 alkyl, C(=O )C _1-4 alkyl, -(CH ₂ ) _0-1 -C(=O)OH, -C(=O)OC _1-4 alkyl, -S(=O) ₂ C _1-4 alkyl, and - NHC(=O)OC _1-4 alkyl;

R ^3c is independently selected from H, CF ₂ H, CF ₃ , C _1-4 alkyl, and CD ₃ ;

R ⁴ is independently selected from H, F, and C _1-4 alkyl;

R ⁷ is H;

wherein the other variable is as defined in formula IIa above.

Provided are compounds of Formula IIa, or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

In another aspect, the invention provides a compound of Formula (V) or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

<Formula V>

In the above equation

Ring A is independently selected from phenyl and 5- to 6-membered heterocyclyl;

W is independently selected from CHR ^1a , O, NH, and N(C _1-4 alkyl);

R ¹ is independently selected from H and C _1-4 alkyl;

R ^1a is independently selected from H and F;

R ² is independently selected from H and hydroxyl;

R ³ is independently H, haloalkyl, and C _1-4 alkyl (optionally substituted with R ⁶ ), F, CN, C(=O)C _1-4 alkyl, C(=O)OH, -S( =O) ₂ C _1-4 alkyl, and -NHC(=O)OC _1-4 alkyl;

R ⁴ is independently selected from H, OH, F, Cl, Br, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ , and CN;

R ⁵ is independently H, C _1-4 alkyl (optionally substituted with halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino, substituted amino), -(CH ₂ ) _n -C _3-10 carboxy is selected from cryl and -(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with R ⁶ ;

R ⁶ is independently -(CH ₂ ) _n -OH, =O, NH ₂ , -(CH ₂ ) _n -CN, halogen, C _1-6 alkyl, -(CH ₂ ) _n -C(=O)OH , -(CH ₂ ) _n -C(=O)OC _1-4 alkyl, -(CH ₂ ) _n -OC _1-4 alkyl, -(CH ₂ ) _n -C _3-6 cycloalkyl, -(CH ₂ ) is selected from _n -4- to 10-membered heterocyclyl, and -O-(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted with R ¹⁰ become;

R ⁷ is independently selected from H, F, Cl, and methyl;

R ^8b is independently selected from H and F;

R ^8c is independently selected from H, F, Cl, CH ₃ , and OCH ₃ ;

R ¹⁰ is independently H, C _1-6 alkyl (optionally substituted with R ¹¹ ), C _2-6 alkenyl, C _2-6 alkynyl, aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -O-4- to 10-membered heterocyclyl (optionally substituted with R ¹¹ ), F, Cl, Br, CN, NO ₂ , =O, C(=O)NR ¹² R ¹² , C(=O)OR ¹² , Si(C _1-4 alkyl) ₃ , -(CH ₂ ) _n -OR ¹² , and -(CH ₂ ) _n -NR ¹² R ¹² is selected from;

R ¹¹ at each occurrence is independently selected from H, halogen, C _1-5 alkyl, -(CH ₂ ) _n -OH, C _3-6 cycloalkyl, and phenyl;

R ¹² at each occurrence is independently selected from H, C _1-5 alkyl, C _3-6 cycloalkyl, phenyl, and heterocyclyl, or R ¹² and R ¹² are the nitrogen atom to which they are both attached. together form a heterocyclic ring optionally substituted with C _1-4 alkyl;

n is, in each case, an integer independently selected from 0, 1, and 2;

p is, in each case, an integer independently selected from 0, 1, and 2.

In another aspect, the invention provides a compound of Formula VI or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

<Formula VI>

In the above equation

Ring A is independently selected from phenyl and 5- to 6-membered heterocyclyl;

W is independently selected from (CR ¹ R ² ) _1-2 , O, NH, and N(C _1-4 alkyl);

Y is independently selected from -NH-, -NHC(=O)- and -C(=O)NH-;

R ¹ and R ² are independently selected from H, halogen, CF ₃ , C _1-6 alkyl, and hydroxyl;

R ³ is independently H, haloalkyl, and C _1-4 alkyl (optionally substituted with R ⁶ ), -(CH ₂ ) _0-2 -OH, C(=O)C _1-4 alkyl, -(CH ₂ ) _0-2 -C(=O)OH, and -C(=O)OC _1-4 alkyl; Only one R ^3c is present on the ring;

R ⁴ is independently H, OH, F, Cl, Br, C _1-4 alkyl, C _1-4 alkoxy, CF ₃ , CN, C _3-6 cycloalkyl, aryl, and 5- to 6-membered heterocycle selected from ryl, wherein said cycloalkyl, aryl and heterocyclyl are optionally substituted with R ⁶ ;

R ⁵ is independently H, C _1-4 alkyl (optionally substituted with halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl, amino, substituted amino), -(CH ₂ ) _n -C _3-10 carboxy is selected from cryl and -(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with R ⁶ ;

R ⁶ is independently -(CH ₂ ) _n -OH, =O, NH ₂ , -(CH ₂ ) _n -CN, halogen, C _1-6 alkyl, -(CH ₂ ) _n -C(=O)OH , -(CH ₂ ) _n -C(=O)OC _1-4 alkyl, -(CH ₂ ) _n -OC _1-4 alkyl, -(CH ₂ ) _n -C _3-6 cycloalkyl, -(CH ₂ ) is selected from _n -4- to 10-membered heterocyclyl, and -O-(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted with R ¹⁰ become;

R ⁷ is independently selected from H, F, and methyl;

R ^8a is independently H, F, Cl, Br, CN, OCH ₃ , OCF ₃ , CH ₃ , C(=O)CH ₃ , CHF ₂ , CF ₃ , CCH ₃ F ₂ , OCHF ₂ , aryl, C _{3 -6} cycloalkyl, and 4- to 6-membered heterocyclyl optionally substituted with R ¹⁰ ;

R ^8b is independently selected from H and F;

R ^8c is independently selected from H, F, Cl, CH ₃ , and OCH ₃ ;

R ¹⁰ is independently H, C _1-6 alkyl (optionally substituted with R ¹¹ ), C _2-6 alkenyl, C _2-6 alkynyl, aryl, -(CH ₂ ) _n -C _3-6 cycloalkyl (optionally substituted with R ¹¹ ), -(CH ₂ ) _n -O-4- to 10-membered heterocyclyl (optionally substituted with R ¹¹ ), F, Cl, Br, CN, NO ₂ , =O, is selected from CONR ¹² R ¹² , C(=O)OR ¹² , Si(C _1-4 alkyl) ₃ , -(CH ₂ ) _n -OR ¹² , and -(CH ₂ ) _n -NR ¹² R ¹² ;

R ¹¹ at each occurrence is independently selected from H, halogen, C _1-5 alkyl, -(CH ₂ ) _n -OH, C _3-6 cycloalkyl, and phenyl;

R ¹² at each occurrence is independently selected from H, C _1-5 alkyl, C _3-6 cycloalkyl, phenyl, and heterocyclyl, or R ¹² and R ¹² are the nitrogen atom to which they are both attached. together form a heterocyclic ring optionally substituted with C _1-4 alkyl;

n is, in each case, an integer independently selected from 0, 1, and 2;

p is, in each case, an integer independently selected from 0, 1, and 2.

로 이루어진 군으로부터 선택되고, 여기서 R⁸은 독립적으로 각 경우에, H, 할로겐, CN, C_1-6 알킬, 할로알킬, 알콕시, 할로알콕시, 및 4- 내지 6-원 헤테로시클릴로 이루어진 군으로부터 선택된다.In one embodiment, G ¹ is independently

is selected from the group consisting of, where R ⁸ is independently at each occurrence, from the group consisting of H, halogen, CN, C _1-6 alkyl, haloalkyl, alkoxy, haloalkoxy, and 4- to 6-membered heterocyclyl. is selected.

이고, 여기서 R⁸은 독립적으로 각 경우에, H, 할로겐, CN, 메틸, 에틸, CF₃ CHF₂, OMe, OEt, OCF₃, OCHF₂, 아릴, C_3-6 시클로알킬, 및 4- 내지 6-원 헤테로시클릴로 이루어진 군으로부터 선택된다.In another embodiment, G ¹ is

and wherein R ⁸ is independently at each occurrence H, halogen, CN, methyl, ethyl, CF ₃ CHF ₂ , OMe, OEt, OCF ₃ , OCHF ₂ , aryl, C _3-6 cycloalkyl, and 4- to is selected from the group consisting of 6-membered heterocyclyl.

이며,In another embodiment, G ¹ is

and

is selected from the group consisting of

이고, 여기서 R^8a는 독립적으로 H, F, OCH₃, OCHF₂, 및

로 이루어진 군으로부터 선택된다.In another embodiment, G ¹ is

, where R ^8a is independently H, F, OCH ₃ , OCHF ₂ , and

is selected from the group consisting of

In another embodiment, R ^8b is independently selected from the group consisting of H, F and Cl.

In another embodiment, R ^8b is independently selected from the group consisting of H and F.

In another embodiment, R ^8c is Cl.

이며,In another embodiment, G ¹ is

and

is selected from the group consisting of

이다.In another embodiment, G ¹ is

am.

In one embodiment, the invention provides formulas I, II, IIa, IIb, wherein Ring A is independently selected from the group consisting of imidazole, oxadiazole, pyridine, pyridinone, pyridazine, pyridazinone, and phenyl. Provided are compounds of IIc, IId, IIe, IIf, IIg, IIIa, IIIb, IVb, V, and VI, or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

는 독립적으로In another embodiment,

is independently

is selected from the group consisting of

는 독립적으로In another embodiment,

is independently

is selected from the group consisting of

는 독립적으로In another embodiment,

is independently

is selected from the group consisting of

는 독립적으로In another embodiment,

is independently

is selected from the group consisting of

는

이다.In another embodiment,

Is

am.

는

이다.In another embodiment,

Is

am.

는

이다.In another embodiment,

Is

am.

는

이다.In another embodiment,

Is

am.

는

이다.In another embodiment,

Is

am.

는

이다.In another embodiment,

Is

am.

는

이다.In another embodiment,

Is

am.

In another embodiment, ring B is independently

is selected from

In another embodiment, ring B is independently

z,

is selected from

In another embodiment, ring B is independently

is selected from

이고, 여기서 R^3c는 독립적으로 H, CHF₂, CD₃, CH₃, 및 SO₂CH₃으로부터 선택된다.In another embodiment, Ring B is

and where R ^3c is independently selected from H, CHF ₂ , CD ₃ , CH ₃ , and SO ₂ CH ₃ .

In another embodiment, R ¹ is independently selected from the group consisting of H, OH, F, and C _1-4 alkyl.

In another embodiment, R ¹ is independently selected from the group consisting of H and methyl, ethyl, and isopropyl.

In one embodiment, R ² is independently, at each occurrence, selected from the group consisting of H and C _1-4 alkyl.

In another embodiment, R ² is independently, at each occurrence, selected from the group consisting of H and methyl.

In another embodiment, one of R ¹ and R ² is H and the other is methyl.

In another embodiment, R ¹ and R ² together are =O.

In one embodiment, Ring B is a 5-membered heteroaryl comprising a carbon atom and a heteroatom selected from N and NR ^3c ; R ³ is independently H, halogen, C _1-4 alkyl (optionally substituted with R ⁶ ), CN, -(CH ₂ ) _n -OR ⁵ , -(CH ₂ ) _n -NR ⁵ R ⁵ , -(CH ₂ ) _n -C(=O)R ⁵ , and -(CH ₂ ) _n -C(=O)OR ⁵ ; R ^3c is independently H, haloalkyl, C _1-4 alkyl (optionally substituted with R ⁶ ), -(CH ₂ ) _1-2 -OH, C(=O)C _1-4 alkyl, -(CH ₂ ) _1-2 -C(=O)OH, -C(=O)OC _1-4 alkyl, S(=O) _p C _1-6 alkyl, -(CH ₂ ) _n -C _3-10 carbocyclyl and -(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein the carbocyclyl and heterocyclyl are optionally substituted with R ⁶ ; R ⁵ is independently H, C _1-4 alkyl (optionally substituted with halogen, hydroxyl, alkoxy, carboxy, alkoxycarbonyl), -(CH ₂ ) _n -C _3-10 carbocyclyl and -(CH ₂ ) is selected from _n -4- to 10-membered heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted with R ⁶ ; R ⁶ is independently OH, =O, -(CH ₂ ) _n NH ₂ , -(CH ₂ ) _n CN, halogen, C _1-6 alkyl, -(CH ₂ ) _n -C(=O)OH, - (CH ₂ ) _n -C(=O)OC _1-4 alkyl, -(CH ₂ ) _n -OC _1-4 alkyl, -(CH ₂ ) _n -C _3-10 carbocyclyl, -(CH ₂ ) is selected from _n -4- to 10-membered heterocyclyl, and -(CH ₂ ) _n -4- to 10-membered heterocyclyl, wherein the carbocyclyl and heterocyclyl are optionally substituted with R ¹⁰ .

In another aspect, the invention provides compounds selected from the list of any subset of the compounds exemplified in this application.

In another aspect, the invention provides a compound selected from:

(9R,13S)-13-(4-{5-chloro-2-[(pyrimidin-2-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- on;

Ethyl 2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^{2 ,6} ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)- 1H-pyrazol-1-yl]acetate;

2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H -pyrazol-1-yl]acetic acid;

2-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)acetonitrile;

(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene -8-on;

(9R,13S)-13-{4-[5-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine- 1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16- pentaen-8-one trifluoroacetate;

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10-methyl-4,5,8-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3 ,5,15,17-hexaen-9-one;

1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazole -4-carboxylic acid;

(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-5-chloro-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1,3-thiazol-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidine -1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6 ),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 ,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] Octadeca-1(18),2( 6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18) ,2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18) ,2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9S,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- on trifluoroacetate;

(9R,13S)-13-{4-[3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4,14,16-penta en-8-one trifluoroacetate;

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ),4,14,16-pentaen-8-one;

(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-16-fluoro-3 ,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4,14 ,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14, 16-pentaen-8-one;

(9R)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydro Pyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16 -pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo[ _12.3.1.0 ^2,6 ]octadeca-1(18),2( 6),4,14,16-pentaen-8-one;

(10R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-10-methyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5 ,15,17-hexaen-9-one trifluoroacetate;

1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3 -fluorophenyl)-1H-1,2,3-triazole-4-carbonitrile;

(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-( ^2H ₃ )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1( 18),2(6),4,14,16-pentaen-8-one;

1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-( ^2H ₃ )methyl-9-methyl-8-oxo-3,4,7-triazatri Cyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidine-4 -yl}phenyl)-1H-1,2,3-triazole-4-carbonitrile;

1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl) -1H-1,2,3-triazole-4-carbonitrile;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-8-one;

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5 ,15,17-hexaen-9-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, 14,16-pentaen-8-one;

(9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo[ _12.3.1.0 ^2,6 ]octadeca-1(18),2 (6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(pyrimidin-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6- Oxo-1,6-dihydropyrimidin _- 1-yl)-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca- 1(18),2(6),4,14,16-pentaen-8-one;

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4,10-dimethyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3 ,5,15,17-hexaen-9-one;

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-5-methoxy-10-methyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2(7) ),3,5,15,17-hexaen-9-one;

(10R,14S)-5-Chloro-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}- 6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2(7) ,3,5,15,17-hexaen-9-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,16-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, 14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18 ),2(6),4,14,16-pentaene-16-carboxamide;

1-(4-chloro-2-{1-[(9R,13S)-3-( ^2H ₃ )methyl-9-methyl-8-oxo-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl) -1H-1,2,3-triazole-4-carboxamide;

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 ,14,16-pentaen-8-one;

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) ,2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), 2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) ,2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2 (6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

2-[(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6 -Oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1( 18),2(6),4,14,16-pentaen-3-yl]acetic acid trifluoroacetate;

2-[(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6 -Oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] Octadeca-1( 18),2(6),4,14,16-pentaen-3-yl]acetic acid trifluoroacetate;

2-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1, 6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2( 6),4,14,16-pentaen-3-yl]acetic acid trifluoroacetate;

2-[(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ,4,14,16-pentaen-3-yl]acetic acid trifluoroacetate;

2-[(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6 -Oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-3-yl]acetic acid trifluoroacetate;

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ,4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14, 16-pentaen-8-one trifluoroacetate;

Methyl (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),3,5, 14,16-pentaene-4-carboxylate trifluoroacetate;

Methyl (9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo -1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ] octadeca-1 (18) ,3,5,14,16-pentaene-4-carboxylate trifluoroacetate;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),3,5,14 ,16-pentaene-4-carboxylic acid trifluoroacetate;

(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1 (18), 3,5,14,16-pentaene-4-carboxylic acid trifluoroacetate;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-3-( ^2H3 )methyl-9 _- methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18), 2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-( ^2H3 )methyl-9-methyl-3,4,7,15 _- tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2( 6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl (10,11- ² H ₂ )-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ] octa Deca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-( ^2H ₃ )methyl-9-methyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]Octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-10-methyl-3,8,16-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15, 17-hexaen-9-one, bis-trifluoroacetate;

(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3- ( ² H ₃ )methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16- pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidine- 1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4 ,14,16-pentaen-8-one;

(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3- (difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaene -8-on;

(10R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-10-methyl-3,8,16-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3 ,5,15,17-hexaen-9-one bis-trifluoroacetate;

(9R,13S)-3-(difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethyl)-1H-1,2,3-tria zol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,17-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-5-(trifluoromethyl)- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6),4,14,16-pentaen-8-one;

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10-methyl-3,8,16-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3 ,5,15,17-hexaen-9-one, bis-trifluoroacetate;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), 2(6),4,14,16-pentaen-8-one;

6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S)-3,9- Dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-3 ,4-dihydropyrimidin-4-one;

(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-10-fluoro-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-11-fluoro-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-8-one;

(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-10,16-difluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2 (6),4,14,16-pentaen-8-one;

(9S,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10,16-difluoro-3,9-dimethyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ] octadeca-1 (18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo[ _12.3.1.0 ^2,6 ] octadeca-1(18),2 (6),4,14,16-pentaen-8-one;

6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S)-3-(di Fluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene -13-yl]-3,4-dihydropyrimidin-4-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18 ),2(6),4,14,16-pentaene-16-carbonitrile;

(9R,13S)-13-(4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1, 6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6) ,4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl- 3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidine- 1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16- pentaen-8-one trifluoroacetate;

(13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 ,14,16-pentaen-8-one trifluoroacetate;

(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), 2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), 2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-3-(difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethyl)-1H-1,2,3-tria zol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4 ,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydro Pyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14 ,16-pentaen-8-one;

(9R,13S)-13-[4-(3-fluoro-4-methylpyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), 2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, 14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2( 6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 ,14,16-pentaen-8-one trifluoroacetate;

1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1, 2,3-triazole-4-carboxamide trifluoroacetate;

1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1, 2,3-triazole-4-carbonitrile trifluoro acetate;

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2(7) ,3,5,15,17-hexaene-5-carbonitrile;

(9R,13S)-13-(4-{5-chloro-2-[4-({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy}methyl) -1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15 -tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-(4-{5-chloro-2-[4-(hydroxylmethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1 ,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6) ),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] Octadeca-1(18),2( 6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-oxo-1,6-dihydro Pyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14 ,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-(4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1 ,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6) ),4,14,16-pentaen-8-one trifluoroacetate;

1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl} phenyl)-1H-1,2,3-triazole-4-carbonitrile trifluoroacetate;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-( ^2H3 )methyl-9-methyl-3,4,7,15 _- tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-( ^2H ₃ )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1( 18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9S,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6),4,14,16-pentaen-8-one;

(9R,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(pyridin-3-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9- dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]phenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-3-(difluoromethyl)-9-methyl-13-(6-oxo-4-{2-[4-(trifluoromethyl)-1H-1,2,3-tria zol-1-yl]phenyl}-1,6-dihydropyrimidin-1-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) ,2(6),4,14,16-pentaen-8-one;

(9R,13S)-3-(difluoromethyl)-13-(4-{5-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1 -yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 ,14,16-pentaen-8-one trifluoroacetate;

5-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)pyridine-3-carboni trill;

(9R,13S)-13-{4-[5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 ,14,16-pentaen-8-one trifluoroacetate;

Methyl 4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}benzoate;

(9R,13S)-13-{4-[3-chloro-6-(4-ethoxy-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo -1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2 (6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo -1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2 (6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4,14,16-pentaene-8- Ontrifluoroacetate;

(9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo -1,6-dihydropyrimidin-1 _- yl}-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl) -1H-1,2,3-triazole-4-carbonitrile trifluoroacetate;

(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3-( ^2H ₃ )methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl} -3-fluorophenyl)-1H-1,2,3-triazole-4-carbonitrile trifluoroacetate;

(9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo -1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-(4-{3-chloro-6-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]-2-fluorophenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-(4-{3-chloro-6-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]-2-fluorophenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-[4-(3-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15- tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1 (18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}benzoic acid;

(9R,13S)-3-(difluoromethyl)-9-methyl-13-{6-oxo-4-[5-(propan-2-yl)-2-[4-(trifluoromethyl) -1H-1,2,3-triazol-1-yl]phenyl]-1,6-dihydropyrimidin-1-yl}-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-( ^2H3 )methyl-9-methyl-3,4,7,17 _- tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,14,16-pentaene-16-carbonitrile;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2( 6),4,14,16-pentaen-8-one;

(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2( 6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-3-(difluoromethyl)-13-(4-{5-ethyl-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1- yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one;

(9S,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{5-chloro-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1 ,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6) ),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-3-(difluoromethyl)-13-(4-{4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1 -yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-( ^2H3 )methyl-9 _- methyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18), 2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoro Methyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8 -on;

(9R,13S)-13-[4-(5-chloro-2-phenylphenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4, 7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-[4-(5-chloro-1-ethyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3- (difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16- pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ,4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1, 6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ,4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1, 6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1 (18) ,2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[5-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), 2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6) ,4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-fluoro-6-oxo- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2( 6),4,14,16-pentaen-8-one;

(9R,13S)-13-{5-bromo-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2( 6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-3-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10-methyl-5,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5 ,15,17-hexaen-9-one;

(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-10-methyl-5,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15,17- hexaen-9-one;

(9R,13S)-13-[4-(6-chloro-1H-1,3-benzodiazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3 -(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16 -pentaen-8-one;

Methyl 4-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1 ,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2 ,5,14,16-pentaen-4-yl]piperidine-1-carboxylate;

(9R,13S)-13-(4-{4-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo-1 ,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6) ),4,14,16-pentaen-8-one;

(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4 ,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2( 6),4,14,16-pentaen-8-one trifluoroacetate;

N-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl) carbamate trifluoroacetate;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1 (18),2(6),4,14,16-pentaen-15-ium-15-oleate;

(9R,13S)-13-(4-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo -1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1 (18),2(6),4,14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-methyl-4-(pyridin-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18) ,2,5,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-methyl-3-(pyridin-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18) ,2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin-3-yl}- 6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(5-bromo-4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin- 3-yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1 (18), 2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{4,5-dichloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6- Oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-4-(1-methyl-1H-imidazol-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2,5,14,16-pentaen-8-one;

4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1 (18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-N-(2,2,2- trifluoroethyl)benzamide;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),3, 14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2( 6),3,14,16-pentaen-8-one;

(9R,13S)-13-[4-(1-benzyl-5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3- (difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16- pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4, 14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-pyrazol-3-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene -8-on;

(9R,13S)-13-{4-[5-chloro-2-(1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3 ,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one ;

(9R,13S)-13-[4-(5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoro Methyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8 -on;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-4-(6-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- 1(18),2,5,14,16-pentaen-8-one;

(10R,14S)-3-chloro-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1 ,6-dihydropyrimidin-1-yl}-10-methyl-5,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5, 15,17-hexaen-9-one;

(9R,13S)-13-{4-[5-chloro-2-(1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3 ,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one ;

N-benzyl-4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}benzamide;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-methyl-4-(pyridin-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18) ,2,5,14,16-pentaen-8-one;

1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-( ^2H ₃ )methyl-9-methyl-8-oxo-3,4,7,15-tetra Azatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidine -4-yl}phenyl)-1H-pyrazole-4-carbonitrile;

1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl} -3-fluorophenyl)-1H-pyrazole-4-carbonitrile;

(9R,13S)-13-{4-[5-chloro-2-(1-propyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene -8-on;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-methyl-4-(pyridin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18) ,2,5,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-methyl-3-(pyridin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18) ,2(6),4,14,16-pentaen-8-one;

1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imidazole -4-carbonitrile;

N-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl} phenyl)-2,2,2-trifluoroacetamide;

(9R,13S)-13-(4-{5-chloro-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-di Hydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, 14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-(difluoromethoxy)-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl] -6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-3-(difluoromethyl)-13-(4-{5-methoxy-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1 -yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[1-(2-methylpropyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydro Pyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14 ,16-pentaen-8-one;

(9R,13S)-13-{4-[2-(1-benzyl-1H-pyrazol-4-yl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene -8-on;

(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4, 14,16-pentaen-8-one;

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-fluoro-10-methyl-5,8,16-triazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2 (7),3,5,15,17-hexaen-9-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyridin-2-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2,5,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2,5,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4,14,16-penta en-8-on;

(9R,13S)-13-(4-{5-chloro-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] Octadeca-1(18),2( 6),4,14,16-pentaen-8-one;

3-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1, 6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2, 5,14,16-pentaen-4-yl]benzonitrile;

(9R,13S)-13-{4-[5-chloro-2-(5-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene -8-one trifluoroacetate;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-methyl-4-(1H-pyrazol-3-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1 (18),2,5,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18 ),2,5,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-9-methyl-4-(pyrazin-2-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca -1(18),2,5,14,16-pentaen-8-one;

(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9 -methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{3-chloro-6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluorophenyl}-6-oxo-1 ,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ),4,14,16-pentaen-8-one;

(9R,13S)-13-[4-(5-chloro-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl )-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- on;

(9R,13S)-13-[4-(6-chloro-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoro Methyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8 -on;

(14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1, 6-dihydropyrimidin-1-yl)-10-methyl-5,8,16-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5 ,15,17-hexaen-9-one trifluoroacetate;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-9-methyl-4-(6-oxo-1,6-dihydropyridazin-4-yl)-3,4,7,15-tetraazatri Cyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyrazin-2-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2,5,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-methoxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[ 12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,14,16-pentaene-17-carbonitrile;

(9R,13S)-13-{4-[5-chloro-2-(4-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene -8-on;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-hydroxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[ 12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(1,3-oxazol-2-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl} -3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8 -on;

(9R,13S)-13-(4-{5-chloro-2-[(pyrazin-2-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3 ,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one ;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(4-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2,5,14,16-pentaen-8-one;

Ethyl 1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-3-methyl -1H-pyrazole-4-carboxylate;

(9R,13S)-13-{4-[5-chloro-2-(3,4-dimethyl-1H-pyrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidine- 1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16- pentaen-8-one;

Ethyl 1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyra sol-4-carboxylate;

(9R,13S)-13-[4-(5-chloro-2-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4 ,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}-6-oxo-1,6-dihydro Pyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] Octadeca-1(18),2(6),4,14 ,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-4-methanesulfonyl-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2,5 ,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-methanesulfonyl-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}- 6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

Methyl 1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imi Dazole-4-carboxylate;

(9R,13S)-13-[4-(2,5-dichlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7, 15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13R)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, 14,16-pentaen-8-one trifluoroacetate;

(9R,13S)-13-(4-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}- 6-oxo-1,6-dihydropyrimidin-1-yl)-3-( ^2H ₃ )methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imidazole -4-carboxylic acid;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, 14,16-pentaen-8-one;

(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-10-methyl-3,5,8-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15, 17-hexaen-9-one;

(9R,13S)-13-{4-[5-chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,14,16-pentaen-8-one;

(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-( difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-penta en-8-on;

(9R,13S)-13-{4-[5-chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,14,16-pentaen-8-one;

(9R,13S)-13-[4-(6-chloro-1-methyl-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3- (difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16- pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-4-(6-hydroxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- 1(18),2,5,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-oxo-1 ,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ),4,14,16-pentaen-8-one;

(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-3, 4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-penta en-8-on;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(2-hydroxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2,5,14,16-pentaen-8-one;

(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-4- (pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaene-8- on;

(9R,13S)-13-{4-[5-chloro-2-(pyridazin-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9 -dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-4-(2-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca -1(18),2,5,14,16-pentaen-8-one;

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,17-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3 ,5,15,17-hexaen-9-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-methyl-4-(piperidin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1( 18),2,5,14,16-pentaen-8-one;

1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl) -1H-pyrazole-4-carbonitrile;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-4-(1H-imidazol-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1 (18),2,5,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-methyl-4-(1H-1,2,4-triazol-5-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^{2, 6} ]octadeca-1(18),2,5,14,16-pentaen-8-one;

N-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2, 2-trifluoroacetamide;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(2-hydroxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2,5,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-methyl-3-(1H-pyrazol-3-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1 (18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4, 7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[(pyrimidin-4-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- on;

(9R,13S)-13-{4-[2-(aminomethyl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl )-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- on;

(9R,13S)-13-{4-[5-chloro-2-(pyridin-2-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9- dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2,5,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(6-methoxypyrimidin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyrimidin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2,5,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(6-hydroxypyrimidin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2,5,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2,5,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-methylphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl- 3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(3-chlorophenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(3-methoxyphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9- dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(2-methylphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl- 3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethoxy)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4,14,16-pentaene-8- on;

(9R,13S)-13-{4-[5-chloro-2-(2-chlorophenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- on;

(9R,13S)-13-(4-{5-chloro-2-[4-(propan-2-ylsulfanyl)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl )-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene- 8-on;

4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzene-1-sulfone amides;

(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethoxy)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- on;

N-[3-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)phenyl] methanesulfonamide;

3-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzonitrile;

(9R,13S)-13-(4-{5-chloro-2-[3-(trifluoromethoxy)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4,14,16-pentaene-8- on;

(9R,13S)-13-{4-[5-chloro-2-(3-methanesulfonylphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9 -dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

Methyl 4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzoate;

(9R,13S)-13-{4-[5-chloro-2-(3-methylphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl- 3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzonitrile;

(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-indol-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl }-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene- 8-on;

(9R,13S)-13-{4-[5-chloro-2-(isoquinolin-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9 -dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

Methyl 3-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzoate;

N-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)phenyl] methanesulfonamide;

(9R,13S)-13-(4-{5-chloro-2-[3-(trifluoromethyl)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- on;

(9R,13S)-13-{4-[5-chloro-2-(4-methoxyphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9- dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(4-chlorophenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(pyridin-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9- dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(isoquinolin-7-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9 -dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

(9R,13S)-13-{4-[5-chloro-2-(pyrimidin-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9 -dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one;

Ethyl 2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^{2 ,6} ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)- 1H-pyrazol-1-yl]acetate;

(9R,13S)-13-{4-[5-chloro-2-(1-ethyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene -8-on; and

(9R,13S)-13-(4-{5-chloro-2-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-di Hydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, 14,16-pentaen-8-one.

In another embodiment, the compounds of the invention have a factor XIa or plasma kallikrein Ki value ≤ 10 μM.

In another embodiment, the compounds of the invention have a factor XIa or plasma kallikrein Ki value ≤ 1 μM.

In another embodiment, the compounds of the invention have a factor XIa or plasma kallikrein Ki value ≤ 0.5 μM.

In another embodiment, the compounds of the invention have a factor XIa or plasma kallikrein Ki value ≤ 0.1 μM.

II. Other Embodiments of the Invention

In another embodiment, the invention provides a composition comprising at least one of a compound of the invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of a compound of the invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

In another embodiment, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof. do.

In another embodiment, the invention provides a method of preparing the compounds of the invention.

In another embodiment, the invention provides intermediates for preparing the compounds of the invention.

In another embodiment, the invention provides pharmaceutical compositions further comprising additional therapeutic agent(s). In a preferred embodiment, the invention provides pharmaceutical compositions wherein the additional therapeutic agent(s) is an antiplatelet agent or a combination thereof. Preferably, the antiplatelet agent(s) is clopidogrel and/or aspirin, or a combination thereof.

In another embodiment, the invention provides a therapeutically effective amount of a compound of the invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, to a patient in need of treatment and/or prevention of a thromboembolic disorder. A method for treating and/or preventing a thromboembolic disorder is provided, comprising administering at least one kind.

In another embodiment, the invention provides a compound of the invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, for use in therapy.

In another embodiment, the invention provides a compound of the invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof, for use in therapy for the treatment and/or prevention of thromboembolic disorders. do.

In another embodiment, the present invention also provides a pharmaceutical composition for the preparation of a medicament for the treatment and/or prevention of thromboembolic disorders, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof. Provides a purpose.

In another embodiment, the invention comprises administering a therapeutically effective amount of a first and a second therapeutic agent to a patient in need of treatment and/or prevention of a thromboembolic disorder, wherein the first therapeutic agent is a compound of the invention. or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, and the second therapeutic agent is a factor Provided is a method for the treatment and/or prevention of thromboembolic disorders comprising at least one agent selected from dabigatran, a thrombolytic agent and a fibrinolytic agent. Preferably, the second therapeutic agent is warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatroban, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxy Calm, diclofenac, erivacban, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, melagatran, desulfatohirudin, tissue plasminogen activator, modified At least one agent selected from tissue plasminogen activator, anistreplase, urokinase, and streptokinase. Preferably, the second therapeutic agent is at least one antiplatelet agent. Preferably, the antiplatelet agent(s) is clopidogrel and/or aspirin, or a combination thereof.

Thromboembolic disorders include arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders. Examples of thromboembolic disorders include unstable angina, acute coronary syndrome, atrial fibrillation, primary myocardial infarction, recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, Deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures that expose blood to artificial surfaces that promote thrombosis. Including, but not limited to.

In another embodiment, the invention provides a therapeutically effective amount of a compound of the invention, or at least one of its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates, to a patient in need of treatment and/or prevention of an inflammatory disorder. Provided is a method for treating and/or preventing an inflammatory disorder comprising administering. Examples of inflammatory disorders include, but are not limited to, sepsis, acute respiratory distress syndrome, and systemic inflammatory response syndrome.

In another embodiment, the invention provides a therapeutically effective amount of a compound of the invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, to a patient in need of treatment and/or prevention of a disease or condition in which plasma kallikrein activity has been implicated. , or a solvate.

Diseases or conditions in which plasma kallikrein activity has been implicated include vision impairment, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, and septicemia. Includes, but is not limited to shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, and cardiopulmonary bypass surgery.

In another embodiment, the invention provides a combined preparation of a compound of the invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in therapy.

In another embodiment, the invention provides a combined preparation of a compound of the invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in the treatment and/or prevention of thromboembolic disorders.

The present invention may be implemented in other specific forms without departing from the spirit or essential properties of the present invention. The present invention encompasses all combinations of the preferred aspects of the invention mentioned herein. It is understood that any and all embodiments of the invention may be taken together with any other embodiment or embodiments to describe further embodiments. Additionally, it should be understood that each individual element of the embodiments is its own independent embodiment. Moreover, any element of one embodiment, in combination with any and all other elements from any embodiment, is intended to describe a further embodiment.

III. chemistry

Throughout the specification and appended claims, a given formula or name will encompass all stereo and optical isomers and racemates thereof, if such isomers exist. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the invention. A number of geometric isomers, such as C=C double bonds, C=N double bonds, ring systems, etc., may also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis- and trans- (or E- and Z-) geometric isomers of the compounds of the invention are described, which can be isolated as mixtures of isomers or as separate isomeric forms. Compounds of the invention may be isolated in optically active or racemic forms. Optically active forms can be prepared by resolution of the racemic form or by synthesis from optically active starting materials. All methods used to prepare the compounds of the present invention and intermediates prepared therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods, such as chromatography or fractional crystallization. Depending on the process conditions, the final product of the invention is obtained in free (neutral) or salt form. Both free forms and salts of these final products are within the scope of the present invention. If desired, one form of a compound can be converted to another form. The free base or acid can be converted to a salt; A salt can be converted to the free compound or to another salt; Mixtures of isomeric compounds of the present invention may be separated into individual isomers. The compounds of the invention, their free forms and salts, may exist in multiple tautomeric forms in which the hydrogen atoms are moved to different parts of the molecule and the chemical bonds between the atoms of the molecule are rearranged as a result. It is to be understood that all tautomeric forms, if they may exist, are encompassed within the present invention.

The term “stereoisomer” refers to isomers of the same composition that differ in the arrangement of the atoms in space. Enantiomers and diastereomers are examples of stereoisomers. The term “enantiomer” refers to one of a pair of molecular species that are mirror images of each other and are non-superimposable. The term “diastereomer” refers to stereoisomers that are not mirror images. The term “racemate” or “racemic mixture” refers to a composition consisting of equimolar amounts of two enantiomeric species, wherein the composition is not optically active.

The symbols “R” and “S” indicate the coordination of substituents around the chiral carbon atom(s). The isomeric descriptors “R” and “S” are used as described herein to indicate atomic configuration(s) relative to the core molecule and are described in IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996). ) is intended to be used as defined in

The term “chiral” refers to the structural property of a molecule that renders it incapable of being superimposed on its mirror image. The term “homochiral” refers to a state of enantiomeric purity. The term “optical activity” refers to the degree to which a homochiral molecule, or non-racemic mixture of chiral molecules, rotates the plane of polarized light.

As used herein, the term “alkyl” or “alkylene” is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, “C ₁ to C ₁₀ alkyl” or “C _1-10 alkyl” (or alkylene) means C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , It is intended to include C ₉ , and C ₁₀ alkyl groups. Additionally, for example, “C ₁ to C ₆ alkyl” or “C ₁ -C ₆ alkyl” refers to alkyl having 1 to 6 carbon atoms. An alkyl group can be unsubstituted or substituted by replacing at least one hydrogen with another chemical group. Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl ( Examples include, but are not limited to, n-pentyl, isopentyl, neopentyl). When “C ₀ alkyl” or “C ₀ alkylene” is used, it is intended to indicate a direct bond. “Alkyl” also includes deuteroalkyl such as CD ₃ .

“Alkenyl” or “alkenylene” refers to a hydrocarbon chain in a straight or branched configuration having one or more, preferably one to three, carbon-carbon double bonds that may occur at any stable point along the chain. It is intended to include. For example, “C ₂ to C ₆ alkenyl” or “C _2-6 alkenyl” (or alkenylene) refers to C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ alkenyl groups; It is intended to include, for example, ethenyl, propenyl, butenyl, pentenyl and hexenyl.

“Alkynyl” or “alkynylene” refers to a hydrocarbon chain in a straight or branched configuration having one or more, preferably one to three, carbon-carbon triple bonds that may occur at any stable point along the chain. It is intended to include. For example, “C ₂ to C ₆ alkynyl” or “C _2-6 alkynyl” (or alkynylene) refers to C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ alkynyl groups; It is intended to include, for example, ethynyl, propynyl, butynyl, fentinyl and hexynyl.

The term “alkoxy” or “alkyloxy” refers to the group -O-alkyl. “C ₁ to C ₆ alkoxy” or “C _1-6 alkoxy” (or alkyloxy) is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. Alkoxy also includes deuteroalkoxy such as OCD ₃ . Similarly, "alkylthio" or "thioalkoxy" means an alkyl group as defined above having the indicated number of carbon atoms attached via a sulfur bridge; For example, methyl-S- and ethyl-S-.

“Halo” or “halogen” includes fluoro, chloro, bromo and iodo. “Haloalkyl” is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens. Examples of haloalkyls are fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloro. Including, but not limited to, profiles. Examples of haloalkyl also include "fluoroalkyl", which is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more fluorine atoms.

“Haloalkoxy” or “haloalkyloxy” refers to a haloalkyl group as defined above having the indicated number of carbon atoms attached through oxygen bridges. For example, “C ₁ to C ₆ haloalkoxy” or “C _1-6 haloalkoxy” is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , and C ₆ haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" means a haloalkyl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge; For example, trifluoromethyl-S- and pentafluoroethyl-S-.

As used herein, the term “amino” refers to -NH ₂ .

As used herein, the term “substituted amino” refers to terms defined below having the suffix “amino” such as “arylamino”, “alkylamino”, “arylamino”, etc.

As used herein, the term “alkoxycarbonyl” refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group.

As used herein, the term “alkoxycarbonylamino” refers to -NHR, where R is an alkoxycarbonyl group.

As used herein, the term “alkylamino” refers to -NHR, where R is an alkyl group.

As used herein, the term “alkylcarbonyl” refers to an alkyl group attached to the parent molecular moiety through a carbonyl group.

As used herein, the term “alkylcarbonylamino” refers to -NHR, where R is an alkylcarbonyl group.

As used herein, the term “aminosulfonyl” refers to —SO ₂ NH ₂ .

As used herein, the term “arylalkyl” refers to an alkyl group substituted with 1, 2, or 3 aryl groups.

As used herein, the term “arylamino” refers to -NHR, where R is an aryl group.

As used herein, the term “arylcarbonyl” refers to an aryl group attached to the parent molecular moiety through a carbonyl group.

As used herein, the term “arylcarbonylamino” refers to -NHR, where R is an arylcarbonyl group.

As used herein, the term “cyano” refers to -CN.

As used herein, the term “cycloalkylamino” refers to -NHR, where R is a cycloalkyl group.

As used herein, the term “cycloalkylcarbonyl” refers to a cycloalkyl group attached to the parent molecular moiety through a carbonyl group.

As used herein, the term “cycloalkylcarbonylamino” refers to -NHR, where R is a cycloalkylcarbonyl group.

As used herein, the term “cycloalkyloxy” refers to a cycloalkyl group attached to the parent molecular moiety through an oxygen atom.

As used herein, the term “dialkylamino” refers to NR ₂ wherein each R is an alkyl group. The two alkyl groups may be the same or different.

As used herein, the term “haloalkoxy” refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

As used herein, the term “haloalkyl” refers to an alkyl group replaced by 1, 2, 3 or 4 halogen atoms.

As used herein, the term “haloalkyl amino” refers to -NHR, where R is a haloalkyl group.

The term “carbonyl” refers to C(=O) or C(O).

The term “carboxyl” or “carboxyl” refers to C(=O)OH.

The terms "carboxyl ester" and "oxycarbonyl" refer to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O -Substituted alkenyl, -C(O)O-alkynyl, C(O)O-substituted alkynyl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, - C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heteroxy Refers to click and -C(O)O-substituted heterocyclic.

The term “aminoacyl” or “amide” or the prefix “carbamoyl”, “carboxamide”, “substituted carbamoyl” or “substituted carboxamide” refers to the group -C(O)NRR; where each R is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted is selected from the group consisting of heteroaryl, heterocyclic and substituted heterocyclic.

As used herein, the term “haloalkylcarbonyl” refers to a haloalkyl group attached to the parent molecular moiety through a carbonyl group.

As used herein, the term “haloalkylcarbonylamino” refers to -NHR, where R is a haloalkylcarbonyl group.

The term “alkylcarbonyl” refers to an alkyl or substituted alkyl bonded to a carbonyl.

As used herein, the term “alkoxycarbonyl” refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group.

The term “hydroxy” or “hydroxyl” refers to OH.

As used herein, the term “thiol” means -SH. Thiols may be substituted with substituents disclosed herein, particularly alkyl (thioalkyl), aryl (thioaryl), or alkoxy (thioalkoxy).

As used herein, the term “sulfonyl,” used alone or connected to other terms such as alkylsulfonyl or arylsulfonyl, refers to the divalent radical —SO ₂ —. In the aspect of the present invention, sulfonyl group, sulfonyl group is substituted or unsubstituted hydroxyl, alkyl group, ether group, alkenyl group, alkynyl group, aryl group, cycloalkyl group, cycloalkenyl group, cycloalkynyl group. , can be attached to heterocyclic groups, carbohydrates, peptides or peptide derivatives.

The term “cycloalkyl” refers to a cyclized alkyl group including a mono-, bi-, or poly-cyclic ring system. “C ₃ to C ₇ cycloalkyl” or “C _3-7 cycloalkyl” is intended to include C ₃ , C ₄ , C ₅ , C ₆ , and C ₇ cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of “cycloalkyl”.

As used herein, “carbocycle,” “carbocyclyl,” or “carbocyclic moiety” refers to any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic group. is intended to mean a click or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, unsaturated or May be aromatic. Examples of these carbocyclyls are cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclo Octadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naph. Includes, but is not limited to, thiyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As indicated above, bridged rings are also included in the definition of carbocyclyl (eg, [2.2.2]bicyclooctane). Preferred carbocyclyls, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and indanyl. When the term “carbocyclyl” is used, it is intended to include “aryl”. A bridged ring occurs when one or more carbon atoms join two non-adjacent carbon atoms. Preferred bridges are 1 or 2 carbon atoms. It is noted that crosslinking always converts a monocyclic ring into a tricyclic ring. In case the ring is bridged, the substituents mentioned for the ring may also be present on the bridge.

As used herein, the term "bicyclic carbocyclyl" or "bicyclic carbocyclic group" refers to a stable 9- or 10-membered carbocyclic ring system containing two fused rings and consisting of carbon atoms. It is intended. Of the two fused rings, one ring is a benzo ring fused to the second ring; The second ring is a 5- or 6-membered carbon ring that is saturated, partially unsaturated or unsaturated. A bicyclic carbocyclic group can be attached to its pendant group at any carbon atom that produces a stable structure. Bicyclic carbocyclic groups described herein may be substituted on any carbon provided that the resulting compound is stable. Examples of bicyclic carbocyclic groups include, but are not limited to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons and include, for example, phenyl, naphthyl, and phenanthranyl. Aryl moieties are well known and described, for example, in Lewis, R.J., ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York (1997).

“C ₆ or C ₁₀ aryl” or “C _6-10 aryl” refers to phenyl and naphthyl. Unless otherwise specified, “aryl”, “C ₆ or C ₁₀ aryl” or “C _6-10 aryl” or “aromatic moiety” is unsubstituted or has 1 to 5 groups, preferably 1 to 3 groups. , OH, OCH ₃ , Cl, F, Br, I, CN, NO ₂ , NH ₂ , N(CH ₃ )H, N(CH ₃ ) ₂ , CF ₃ , OCF ₃ , C(=O)CH ₃ , SCH ₃ , S(=O)CH ₃ , S(=O) ₂ CH ₃ , CH ₃ , CH ₂ CH ₃ , CO ₂ H, and CO ₂ CH ₃ may be substituted.

As used herein, the term "benzyl" refers to a methyl group in which one of the hydrogen atoms is replaced by a phenyl group, wherein the phenyl group is one of 1 to 5 groups, preferably 1 to 3 groups, OH, OCH ₃ , Cl, F, Br, I, CN, NO ₂ , NH ₂ , N(CH ₃ )H, N(CH ₃ ) ₂ , CF ₃ , OCF ₃ , C(=O)CH ₃ , SCH ₃ , S(= O)CH ₃ , S(=O) ₂ CH ₃ , CH ₃ , CH ₂ CH ₃ , CO ₂ H, and CO ₂ CH ₃ may be optionally substituted.

As used herein, the term "heterocycle", "heterocyclyl" or "heterocyclic ring" is saturated, partially unsaturated or fully unsaturated and contains 1, 2 carbon atoms and 1, 2 rings independently selected from the group consisting of N, O and S. , stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-membered containing 3 or 4 heteroatoms. -, 13-, or 14-membered polycyclic heterocyclic ring; Any of the heterocyclic rings defined above include any polycyclic group fused to a benzene ring. Nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., N→O and S(O) _p , where p is 0, 1, or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, as defined). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that creates a stable structure. Heterocyclic rings described herein may be substituted on a carbon or nitrogen atom so long as the resulting compound is stable. The nitrogen in the heterocyclyl may be optionally quaternized. When the total number of S and O atoms in the heterocyclyl exceeds 1, it is preferred that these heteroatoms are not adjacent to each other. It is preferred that the total number of S and O atoms in the heterocyclyl is 1 or less. When the term “heterocyclyl” is used, it is intended to include heteroaryl.

Examples of heterocyclyls are acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benzyl. Triazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolyl. Nyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl , isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, Oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl , oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, p. Perazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, Pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, Quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5 -thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thia Zolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1 , 2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. For example, fused ring and spiro compounds containing the above heterocyclyl are also included.

Examples of 5- to 10-membered heterocyclyl include pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, Tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H -indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl , Isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl , oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl, but are not limited thereto.

Examples of 5- to 6-membered heterocyclyls include pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, Including, but not limited to, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl. does not For example, fused ring and spiro compounds containing the above heterocyclyl are also included.

As used herein, the term “bicyclic heterocyclyl” or “bicyclic heterocyclic group” refers to a ring containing two fused rings, carbon atoms and 1, 2 rings independently selected from the group consisting of N, O and S. , is intended to mean a stable 9- or 10-membered heterocyclic ring system consisting of 3 or 4 heteroatoms. Of the two fused rings, one ring is a 5- or 6-membered monocyclic aromatic ring comprising a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, or a benzo ring, each fused to a second ring. do. The second ring is a 5- or 6-membered monocyclic ring that is saturated, partially unsaturated or unsaturated, and is 5-membered heterocyclyl, 6-membered heterocyclyl or carbocyclyl, provided that the second ring is a carbocyclyl where the first ring is not benzo).

A bicyclic heterocyclic group can be attached to its pendant group at any heteroatom or carbon atom that creates a stable structure. Bicyclic heterocyclic groups described herein may be substituted on a carbon or nitrogen atom so long as the resulting compound is stable. When the total number of S and O atoms in the heterocyclyl exceeds 1, it is preferred that these heteroatoms are not adjacent to each other. It is preferred that the total number of S and O atoms in the heterocyclyl is 1 or less.

Examples of bicyclic heterocyclic groups include quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2, 3,4-Tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 2,3-dihydrobenzofuranyl, Chroma Nyl, 1,2,3,4-tetrahydroquinoxalinyl, and 1,2,3,4-tetrahydroquinazolinyl, but are not limited thereto.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl” is intended to mean monocyclic and polycyclic aromatic hydrocarbons containing at least one heteroatom ring member such as sulfur, oxygen or nitrogen. Heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyroyl, Oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl , benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane. Heteroaryl groups may be substituted or unsubstituted. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, as defined). Nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., N→O and S(O) _p , where p is 0, 1, or 2).

Bridged rings are also included in the definition of heterocyclyl. A bridged ring occurs when one or more atoms (i.e., C, O, N, or S) connect two non-adjacent carbon or nitrogen atoms. Examples of bridged rings include, but are not limited to, 1 carbon atom, 2 carbon atoms, 1 nitrogen atom, 2 nitrogen atoms, and carbon-nitrogen groups. It is noted that crosslinking always converts a monocyclic ring into a tricyclic ring. In case the ring is bridged, the substituents mentioned for the ring may also be present on the bridge.

The term “counterion” is used to refer to negatively charged species such as chloride, bromide, hydroxide, acetate and sulfate.

When a dotted ring is used within a ring structure, this indicates that the ring structure may be saturated, partially saturated, or unsaturated.

As used herein, the term “substituted” means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valence is maintained and the substitution results in a stable compound. If the substituent is keto (i.e. =O) then two hydrogens on the atom are replaced. Keto substituents are not present on the aromatic moiety. When a ring system (e.g., carbocyclic or heterocyclic) is referred to as being substituted with a carbonyl group or double bond, it is intended that the carbonyl group or double bond is part of (i.e., internal to) the ring. . As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N or N=N).

If nitrogen atoms (e.g., amines) are present on the compounds of the invention, they can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxide) to provide other compounds of the invention. can do. Accordingly, the presented and claimed nitrogen atoms are considered to encompass both the indicated nitrogen and its N-oxide (N→O) derivatives.

If any variable occurs more than once in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, where a group is indicated to be substituted with 0-3 R groups, said group may optionally be substituted with up to 3 R groups, in each case R being independently selected from the definition of R. Additionally, combinations of substituents and/or variables are permitted only if such combinations result in stable compounds.

When the bond to a substituent is shown to cross the bond connecting two atoms in the ring, such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom by which such substituent is attached to the remainder of the compound of a given formula, such substituent may be attached via any atom within such substituent. Combinations of substituents and/or variables are permitted only if such combinations result in stable compounds.

The phrase “pharmaceutically acceptable” refers to use in contact with human and animal tissues within the scope of sound medical judgment, commensurate with a reasonable benefit/risk ratio, and without excessive toxicity, irritation, allergic reaction, and/or other problems or complications. Used herein to refer to compounds, materials, compositions and/or dosage forms suitable for:

As used herein, “pharmaceutically acceptable salt” refers to a derivative of a disclosed compound in which the parent compound has been modified by preparing an acid or base salt thereof. Examples of pharmaceutically acceptable salts include inorganic or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include, for example, the customary non-toxic salts or quaternary ammonium salts of the parent compounds formed from non-toxic inorganic or organic acids. For example, these common non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, Includes salts prepared from 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid and isethionic acid.

Pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts is found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is incorporated herein by reference.

Additionally, compounds of formula I may have prodrug forms. Any compound that will be converted in vivo to provide a bioactive agent (i.e., a compound of Formula I) is a prodrug within the scope and spirit of the present invention. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:

a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder, K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press (1985);

b) Bundgaard, H., Chapter 5: "Design and Application of Prodrugs", A Textbook of Drug Design and Development, pp. 113-191, Krosgaard-Larsen, P. et al., eds., Harwood Academic Publishers (1991);

c) Bundgaard, H., Adv. Drug Delivery. Rev., 8:1-38 (1992);

d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and

e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

Compounds containing carboxy groups can be hydrolyzed in the body to give themselves compounds of formula (I), thereby forming physiologically hydrolyzable esters that act as prodrugs. These prodrugs are preferably administered orally, since in many cases hydrolysis occurs primarily under the influence of digestive enzymes. Parenteral administration can be used if the ester itself is active or if hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of formula I are C _1-6 alkyl, C _1-6 alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C _1-6 alkanoyloxy- C _1-6 alkyl (e.g. acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), C _1-6 alkoxycarbonyloxy-C _1-6 alkyl (e.g. methoxycarbonyl- oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and for example, Other well-known physiologically hydrolyzable esters used in the penicillin and cephalosporin art. These esters can be prepared by conventional techniques known in the art.

The preparation of prodrugs is well known in the art and is described in, for example, King, F.D., ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, Academic Press, San Diego, CA (1999).

The present invention is intended to include all isotopes of atoms occurring in the compounds of the present invention. Isotopes include atoms with the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium and tritium. Deuterium has one proton and one neutron in its nucleus, and has twice the mass of normal hydrogen. Deuterium may be represented by symbols such as " ^2H " or "D". The term “deuteration” herein, used by itself or to modify a compound or group, refers to the replacement of one or more hydrogen atom(s) attached to a carbon(s) with a deuterium atom. Isotopes of carbon include ¹³ C and ¹⁴ C.

Isotopically-labeled compounds of the invention are generally prepared by conventional techniques known to those of ordinary skill in the art or by methods analogous to those described herein, in place of the otherwise used unlabeled reagents. -Can be prepared using labeled reagents. Such compounds may be used, for example, as standards and reagents in determining the ability of a potential pharmaceutical compound to bind to a target protein or receptor, or for imaging compounds of the invention bound to biological receptors in vivo or in vitro. It has a variety of potential uses.

“Stable compound” and “stable structure” are intended to refer to a compound that is sufficient to withstand isolation from the reaction mixture to a useful degree of purity and to be formulated into an effective therapeutic agent. It is preferred that the compounds of the invention do not contain N-halo, S(O) ₂ H or S(O)H groups.

The term “solvate” refers to the physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. These physical associations include hydrogen bonds. In certain cases, solvates will be isolable, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in the solvate may exist in ordered and/or irregular arrangements. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules. “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are generally known in the art.

Abbreviations used herein are defined as follows: “1 “g” is gram, “mg” is milligram, “L” is liter, “mL” is milliliter, “μL” is microliter, “N” is normal, “M” is mole, “mmol” is millimole, “min” "is minutes, "h" is hours, "rt" is room temperature, "RT" is residence time, "RBF" is round bottom flask, "atm" is atmospheric pressure, "psi" is pounds per square inch, and "conc." is Concentrated, "RCM" for ring-closure metathesis, "sat" or "sat'd" for saturation, "SFC" for supercritical fluid chromatography, "MW" for molecular weight, "mp" for melting point, and "ee" for enantiomeric excess. rate, “MS” or “Mass Spec” for mass spectrometry, “ESI” for electrospray ionization mass spectrometry, “HR” for high resolution, “HRMS” for high resolution mass spectrometry, and “LCMS” for liquid chromatography mass spectrometry. Measurements: “HPLC” for high pressure liquid chromatography, “RP HPLC” for reversed phase HPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” for nuclear magnetic resonance spectroscopy, and “nOe” for nuclear Overhauser effect spectroscopy. Assay, “ ^1H ” is proton, “δ” is delta, “s” is singlet, “d” is doublet, “t” is triplet, “q” is quartet, “m” is multiplet, “ “br” is broad, “Hz” is hertz, and “α”, “β”, “R”, “S”, “E”, and “Z” are stereochemical designations familiar to those skilled in the art. .

The compounds of the present invention can be prepared in a number of ways known to those skilled in the art of organic synthesis, which are described in more detail in Section VI.

IV. biology

Blood coagulation is essential for the regulation of hemostasis in the organism and is also involved in a number of pathological conditions. In thrombosis, a blood clot or thrombus may form and locally block circulation, causing ischemia and organ damage. Alternatively, in a process known as embolism, the clot may dislodge and subsequently become trapped in a distal blood vessel, where it again causes ischemia and organ damage. Diseases resulting from pathological thrombus formation are collectively referred to as thromboembolic disorders and include acute coronary syndrome, unstable angina, myocardial infarction, atrial fibrillation, thrombosis in the cardiac cavity, ischemic stroke, deep vein thrombosis, and peripheral occlusive disease. These include arterial disease, transient ischemic attacks, and pulmonary embolism. Thrombosis also occurs on artificial surfaces that come into contact with blood, including catheters, stents, artificial heart valves, and hemodialysis membranes.

Some conditions contribute to the risk of developing thrombosis. For example, changes in blood vessel walls, changes in blood flow, and changes in the composition of vascular compartments. These risk factors are collectively known as the Virchow triad. (Colman, R.W. et al., eds., Hemostasis and Thrombosis, Basic Principles and Clinical Practice, Fifth Edition, p. 853, Lippincott Williams & Wilkins (2006)).

Antithrombotic agents are frequently given to patients at risk of developing thromboembolic disease due to the presence of one or more risk factors from the Virjo triad to prevent the formation of occlusive thrombi (primary prevention). For example, in orthopedic surgical settings (e.g., hip and knee replacements), antithrombotic agents are frequently administered prior to surgical procedures. Antithrombotic agents counteract the prothrombotic stimulus exerted by changes in blood composition due to vascular flow alterations (stasis), potential surgical vessel wall damage, as well as acute phase reactions associated with surgery. Another example of using an antithrombotic agent for primary prevention is the administration of aspirin, a platelet activation inhibitor, to patients at risk for developing thrombotic cardiovascular disease. Well-recognized risk factors in this setting include advanced age, male gender, hypertension, diabetes, lipid alterations, and obesity.

Antithrombotic agents are also indicated for secondary prevention after the initial thrombotic episode. For example, patients suffering from mutations in factor V (also known as factor V Leiden) and additional risk factors (e.g., pregnancy) are given anticoagulants to prevent recurrence of venous thrombosis. Another example involves secondary prevention of cardiovascular events in patients with a history of acute myocardial infarction or acute coronary syndrome. In the clinical setting, a combination of aspirin and clopidogrel (or another thienopyridine) can be used to prevent secondary thrombotic events.

Additionally, antithrombotic drugs are given to treat a disease state (i.e., by arresting its development) after it has already begun. For example, patients presenting with deep vein thrombosis are treated with anticoagulants (i.e., heparin, warfarin, or LMWH) to prevent further growth of the venous obstruction. Over time, these agents also cause regression of the disease state because the balance between prothrombotic factors and anticoagulant/profibrinolytic pathways changes to tilt towards the latter. Examples pertaining to the arterial vascular bed include treating patients suffering from acute myocardial infarction or acute coronary syndrome with aspirin and clopidogrel to prevent further growth of the vascular occlusion, ultimately causing regression of the thrombotic occlusion.

Accordingly, antithrombotic agents are widely used for primary and secondary prevention (i.e. prevention or risk reduction) of thromboembolic disorders, as well as for treatment of pre-existing thrombotic processes. Drugs that inhibit blood coagulation, or anticoagulants, are “pivotal agents for the prevention and treatment of thromboembolic disorders” (Hirsh, J. et al., Blood, 105:453-463 (2005)).

Alternative modes of coagulation initiation include cell surfaces, cell receptors, It acts on cell debris, DNA, RNA, and extracellular matrix. This process is also named contact activation. Surface absorption of factor XII causes a conformational change in the factor XII molecule, thereby facilitating activation to proteolytically active factor XII molecules (factor Factor XIIa (or XIIf) has multiple target proteins, including plasma prekallikrein and factor XI. Activated plasma kallikrein further activates factor XII, resulting in amplification of contact activation. Alternatively, the serine protease prolylcarboxylpeptidase can activate plasma kallikrein complexed with high molecular weight kininogen in multiprotein complexes formed on the surface and matrix of cells (Sariat-Madar et al., Blood, 108:192-199 (2006)). Contact activation is a surface-mediated process that is partly responsible for the regulation of thrombosis and inflammation and is mediated, at least in part, by fibrinolytic-, complement-, kininogen/kinin-, and other humoral and cellular pathways (reviewed in For, see Coleman, R., "Contact Activation Pathway", Hemostasis and Thrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001); Schmaier, A.H., "Contact Activation", Thrombosis and Hemorrhage, pp. 105 -128 (1998)]. The biological relevance of the contact activation system for thromboembolic diseases is supported by the phenotype of factor XII-deficient mice. More specifically, factor 202:271-281 (2005); Kleinschmitz et al., J. Exp. Med., 203:513-518 (2006). The fact that factor XI is downstream from factor XIIa, combined with the identical phenotypes of XII- and

Factor XI is the zymogen of trypsin-like serine protease and is present in relatively low concentrations in plasma. Proteolytic activation at the internal R369-I370 linkage yields a heavy chain (369 amino acids) and a light chain (238 amino acids). The latter contains typical trypsin-like catalytic triads (H413, D464, and S557). Activation of factor XI by thrombin is believed to occur on negatively charged surfaces, most likely on the surfaces of activated platelets. Platelets contain high affinity (0.8 nM) specific sites (130-500/platelet) for activating factor XI. After activation, Factor XIa remains surface bound and recognizes Factor IX as its normal macromolecular substrate. (Galiani, D., Trends Cardiovasc. Med., 10:198-204 (2000)).

In addition to the feedback activation mechanisms described above, thrombin cleaves C-terminal lysine and arginine residues on fibrin, reducing the ability of fibrin to enhance tissue-type plasminogen activator (tPA)-dependent plasminogen activation. Activates the peptidase, thrombin-activated fibrinolysis inhibitor (TAFI). In the presence of antibodies against FXIa, clot lysis can occur more rapidly, independent of plasma TAFI concentration. (Bouma, B.N. et al., Thromb. Res., 101:329-354 (2001).) Therefore, inhibitors of factor XIa are expected to be anticoagulant and profibrinolytic.

Additional evidence for the anti-thromboembolic effect of targeting factor XI is derived from mice deficient in factor XI. It has been demonstrated that complete fXI deficiency protected mice from ferric chloride (FeCl ₃ )-induced carotid artery thrombosis (Rosen et al., Thromb. Haemost., 87:774-777 (2002); Wang et al. , J. Thromb. Haemost., 3:695-702 (2005)). Additionally, factor XI deficiency rescues the perinatal lethal phenotype of complete protein C deficiency (Chan et al., Amer. J. Pathology, 158:469-479 (2001)). Furthermore, baboon cross-reactive, function-blocking antibodies to human factor Evidence for the antithrombotic effect of small molecule inhibitors of Factor XIa is also disclosed in published US patent application Ser. No. 2004/0180855 A1. Taken together, these studies suggest that targeting factor XI will reduce thrombotic and thromboembolic disease propensity.

Genetic evidence indicates that factor XI is not required for normal homeostasis, suggesting a superior safety profile of the factor Unlike hemophilia A (factor VIII deficiency) or hemophilia B (factor IX deficiency), mutations in the factor It causes only mild to moderate hemorrhagic diathesis. Postoperative bleeding occurs primarily in tissues with high levels of endogenous fibrinolytic activity (eg, oral cavity and genitourinary tract). Most cases are identified incidentally by preoperative prolongation of aPTT (intrinsic system) without any previous history of bleeding.

The increased safety of XIa inhibition as an anticoagulant therapy is further supported by the fact that Factor XI knock-out mice, which do not have any detectable Factor XI protein, undergo normal development and have a normal lifespan. There was no evidence of spontaneous bleeding. aPTT (intrinsic system) extends in a gene dose-dependent manner. Interestingly, even after severe stimulation of the coagulation system (caudal transection), bleeding time is not significantly prolonged when compared to wild type and heterozygous littermates. (Gailani, D., Frontiers in Bioscience, 6:201-207 (2001); Gailani, D. et al., Blood Coagulation and Fibrinolysis, 8:134-144 (1997).) Taken together, these observations suggest that factor This suggests that high levels of inhibitor should be well tolerated. This is contradictory to gene targeting experiments using coagulation factors other than factor XII.

In vivo activation of factor XI can be determined by complex formation with C1 inhibitor or alpha 1 antitrypsin. In a study of 50 patients with acute myocardial infarction (AMI), approximately 25% of patients had values above the upper limit of the normal range for the complex ELISA. The above study can be seen as evidence that, in at least a subset of patients with AMI, factor 2493 (2000)). A second study establishes a positive correlation between the degree of coronary atherosclerosis and factor :1107-1113 (1995)). In another study, factor (2000)).

It is also desirable to discover new compounds with improved activity in in vitro coagulation assays, such as activated partial thromboplastin time (aPTT) or prothrombin time (PT) assays, compared to known serine protease inhibitors. (For a description of the aPTT and PT assays, see Goodnight, S.H. et al., "Screening Tests of Hemostasis", Disorders of Thrombosis and Hemostasis: A Clinical Guide, Second Edition, pp. 41-51, McGraw-Hill, New York (2001)].

It is also desirable and desirable to identify advantageous and improved features compared to known serine protease inhibitors in one or more of the following categories, which are given by way of example and are not intended to be limiting: (a) oral bioavailability, half-life, and pharmacokinetic properties, including clearance; (b) pharmaceutical properties; (c) dosage requirements; (d) factors that reduce the peak-to-trough characteristic of blood levels; (e) factors that increase the concentration of active drug at the receptor; (f) factors that reduce the burden of clinical drug-drug interactions; (g) factors that reduce the potential for adverse side effects, including selectivity for other biological targets; and (h) factors that improve manufacturing cost or feasibility.

Preclinical studies have demonstrated significant antithrombotic effects of small molecule Factor XIa inhibitors in rabbit and rat models of arterial and venous thrombosis, at doses that maintained hemostasis. (Wong P.C. et al., Journal of Thrombosis and Thrombolysis, 32(2):129-137 (Aug. 2011); Schumacher, W. et al., Journal of Thrombosis and Haemostasis, 3(Suppl. 1):P1228 ( 2005); Schumacher, W.A. et al., Eur. J. Pharmacol., 167-174 (2007)). Furthermore, in vitro prolongation of aPTT by specific XIa inhibitors was observed to be a good predictor of efficacy in our thrombosis model. Therefore, the in vitro aPTT test can be used as a surrogate for in vivo efficacy. Preclinical and clinical studies using FXI antisense (ASO) have shown it to be comparable to warfarin or enoxaparin without increased bleeding in various models of venous and arterial thrombosis (Bueller et al., DOI: 10.1056/NEJMoa1405760 ( 2014)).

As used herein, the term “patient” encompasses all mammalian species.

As used herein, “treating” or “treatment” encompasses the treatment of a disease-state in a mammal, particularly a human, and includes (a) inhibiting the disease-state, i.e., preventing its development; and/or (b) alleviating the disease-state, i.e., causing regression of the disease-state.

As used herein, “prophylaxis” refers to reducing the risk of recurrence of a disease state by administering to a patient a therapeutically effective amount of a compound of the invention or at least one of its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates and/ or preventive treatment of a disease state that is minimized. Patients may be selected for prophylactic therapy based on factors known to increase the risk of developing a clinical disease state compared to the general population. In the case of preventive treatment, the pathogenesis of the clinical disease state may or may not yet be present. “Preventive” treatment can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment to reduce or minimize the risk of a disease state in patients who have not yet been shown to have the clinical disease state, whereas secondary prevention is treatment for the development or second occurrence of the same or similar clinical disease state. It is defined as minimizing or reducing risk.

As used herein, “prophylaxis” encompasses prophylactic treatment of subclinical disease-states in mammals, especially humans, aimed at reducing the probability of developing a clinical disease-state. Patients are selected for prophylactic therapy based on factors known to increase the risk of developing a clinical disease state compared to the general population.

As used herein, “risk reduction” encompasses therapies that reduce the incidence of a clinical disease state. Accordingly, primary and secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of a compound of the invention that is effective when administered alone or in combination to inhibit factor XIa and/or plasma kallikrein and/or prevent or treat the disorders listed herein do. When applied to a combination, the term refers to the combined amount of active ingredients that, in combination, produce a prophylactic or therapeutic effect, whether administered sequentially or simultaneously.

As used herein, the term “thrombosis” refers to the formation or presence of a blood clot; Refers to an intravascular coagulation that can cause ischemia or infarction of tissues supplied by blood vessels. As used herein, the term “embolism” refers to the sudden blockage of an artery by a clot or foreign body that has been sent to its site of deposition by the bloodstream. As used herein, the term “thromboembolism” refers to the occlusion of a blood vessel by a thrombotic substance carried by the bloodstream from its original site and occluding another blood vessel. The term “thromboembolic disorder” encompasses both “thrombotic” and “embolic” disorders (as defined above).

As used herein, the term “thromboembolic disorder” includes arterial cardiovascular thromboembolic disorders, venous cardiovascular or cerebrovascular thromboembolic disorders, and thromboembolic disorders in the atrioventricular chambers or in the peripheral circulation. As used herein, the term “thromboembolic disorder” also includes, but is not limited to, unstable angina or other acute coronary syndrome, atrial fibrillation, primary or recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, atherosclerosis. Sclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and medical use where blood is exposed to artificial surfaces promoting thrombosis. Includes certain disorders selected from thrombosis resulting from implants, devices or procedures. Medical implants or devices include, but are not limited to, artificial valves, prosthetic valves, indwelling catheters, stents, blood oxygenators, shunts, vascular access ports, ventricular assist devices and artificial hearts or atrioventricular chambers, and vascular grafts. Procedures include, but are not limited to, cardiopulmonary bypass, percutaneous coronary intervention, and hemodialysis. In another embodiment, the term “thromboembolic disorder” includes acute coronary syndrome, stroke, deep vein thrombosis, and pulmonary embolism.

In another embodiment, the invention provides a method for the treatment of a thromboembolic disorder, wherein the thromboembolic disorder is unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis. Arteriosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and exposure of blood to artificial surfaces that promote thrombosis. Thrombosis resulting from a medical implant, device or procedure. In another embodiment, the invention provides a method for the treatment of thromboembolic disorders, wherein the thromboembolic disorders include acute coronary syndrome, stroke, venous thrombosis, atrial fibrillation, and those resulting from medical implants and devices. Selected from thrombosis.

In another embodiment, the invention provides a method for primary prevention of a thromboembolic disorder, wherein the thromboembolic disorder is unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, sudden ischemic death, transient ischemia. Artificial surfaces that promote stroke, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis. Thrombosis resulting from a medical implant, device or procedure that exposes blood to In another embodiment, the invention provides a method for primary prevention of a thromboembolic disorder, wherein the thromboembolic disorder includes acute coronary syndrome, stroke, venous thrombosis, and thrombosis resulting from medical implants and devices. is selected from

In another embodiment, the invention provides a method for secondary prevention of a thromboembolic disorder, wherein the thromboembolic disorder is unstable angina, acute coronary syndrome, atrial fibrillation, recurrent myocardial infarction, transient ischemic attack. , stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary artery thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and on artificial surfaces that promote thrombosis. Thrombosis resulting from a medical implant, device or procedure to which blood is exposed. In another embodiment, the invention provides a method for secondary prevention of a thromboembolic disorder, wherein the thromboembolic disorder is selected from acute coronary syndrome, stroke, atrial fibrillation, and venous thrombosis.

As used herein, the term “stroke” refers to embolic or atherothrombotic stroke resulting from occlusive thrombosis in the common carotid artery, internal carotid artery, or intracranial artery.

Thrombosis is stated to include vessel occlusion (e.g., after bypass surgery) and re-occlusion (e.g., during or after percutaneous transluminal coronary angioplasty). Thromboembolic disorders result from conditions including, but not limited to, atherosclerosis, surgery or surgical complications, prolonged immobility, atrial fibrillation, congenital thrombophilia, cancer, diabetes, pharmaceutical or hormonal effects, and pregnancy complications. It can be.

Thromboembolic disorders are frequently associated with patients suffering from atherosclerosis. Risk factors for atherosclerosis include, but are not limited to, male gender, advanced age, hypertension, lipid disorders, and diabetes. Risk factors for atherosclerosis are simultaneously risk factors for complications of atherosclerosis, namely thromboembolic disorders.

Similarly, atrial fibrillation is frequently associated with thromboembolic disorders. Risk factors for atrial fibrillation and secondary thromboembolic disorders include cardiovascular disease, rheumatic heart disease, non-rheumatic mitral valve disease, hypertensive cardiovascular disease, chronic pulmonary disease, and various other cardiac abnormalities, as well as thyrotoxicosis.

Diabetes is frequently associated with atherosclerosis and thromboembolic disorders. The more common risk factors for type 2 include family history, obesity, physical inactivity, race/ethnicity, previous impaired fasting glucose or glucose tolerance test, history of gestational diabetes or “large” birth, high blood pressure, low HDL cholesterol, and Including, but not limited to, polycystic ovary syndrome.

Risk factors for congenital thrombophilia include gain-of-function mutations in coagulation factors or loss-of-function mutations in anticoagulant- or fibrinolytic pathways.

Thrombosis has been associated with a variety of tumor types, including pancreatic cancer, breast cancer, brain tumor, lung cancer, ovarian cancer, prostate cancer, gastrointestinal malignancy, and Hodgkin's or non-Hodgkin's lymphoma. Recent studies suggest that the frequency of cancer in patients with thrombosis reflects the frequency of specific cancer types in the general population (Levitan, N. et al., Medicine (Baltimore), 78(5):285-291 (1999); Levine M. et al., N. Engl. J. Med., 334(11):677-681 (1996); Blom, J.W. et al., JAMA, 293(6):715-722 ( 2005)). Accordingly, the most common cancers associated with thrombosis are prostate, colorectal, brain, and lung cancer in men and breast, ovarian, and lung cancer in women. The observed rate of venous thromboembolism (VTE) in cancer patients is significant. The varying VTE rates between different tumor types are most likely related to the selection of the patient population. Cancer patients at risk for thrombosis may have any or all of the following risk factors: (i) stage of cancer (i.e. presence of metastases), (ii) presence of a central venous catheter, (iii) surgery and chemotherapy. anti-cancer therapy, including therapy, and (iv) hormonal and anti-angiogenic drugs. Therefore, administering heparin or low molecular weight heparin to patients with advanced tumors is routine clinical practice to prevent thromboembolic disorders. A number of low molecular weight heparin preparations have been approved by the FDA for these indications.

There are three main clinical situations in which to consider prevention of VTE in medical cancer patients: (i) the patient is bedridden for an extended period of time; (ii) the outpatient is receiving chemotherapy or radiation; (iii) The patient has an indwelling central venous catheter. Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are effective antithrombotic agents in cancer patients undergoing surgery. (Mismetti, P. et al., British Journal of Surgery, 88:913-930 (2001).)

A. In vitro assay

The effectiveness of the compounds of the invention as inhibitors of coagulation factors XIa, VIIa, IXa, Xa, The rate of hydrolysis of chromogenic or fluorogenic substrates by the relevant serine proteases was measured both in the absence and presence of the compounds of the invention. Hydrolysis of the substrate is monitored spectrophotometrically by measuring the increase in absorbance at 405 nm, followed by the release of pNA (paranitroaniline), or spectrofluorometrically by measuring the increase in emission at 460 nm with excitation at 380 nm. This resulted in the release of AMC (amino methylcoumarin), which was monitored. A decrease in the rate of change in absorbance or fluorescence in the presence of an inhibitor indicates enzyme inhibition. These methods are known to those skilled in the art. The results of this assay are expressed as K _i , the inhibition constant.

Factor . The crystals were obtained from purified human factor It was performed using Chromogenix or AnaSpec.

Factor VIIa determinations were performed in 0.05 M HEPES buffer at pH 7.5 containing 0.005 M calcium chloride, 0.15 M sodium chloride, 0.1% PEG 8000. The crystals are purified human Factor VIIa (Hematologic Technologies) or recombinant human Factor VIIa (Novo Nordisk) at a final assay concentration of 0.5-10 nM, recombinant soluble tissue factor at a concentration of 10-40 nM. and the synthetic substrate H-D-Ile-Pro-Arg-pNA (S-2288; Chromogenix or BMPM-2; Anaspec) at concentrations of 0.001-0.0075 M.

Factor IXa determinations were performed in 0.005 M calcium chloride, 0.1 M sodium chloride, 0.0000001 M Refludan (Berlex), 0.05 M TRIS base, and 0.5% PEG 8000 at pH 7.4. Repludan was added to inhibit small amounts of thrombin in a commercial preparation of human factor IXa. The crystals were made using purified human Factor IXa (Hematologic Technologies) at a final assay concentration of 20-100 nM and the synthetic substrate PCIXA2100-B (CenterChem) or Pefafluor at a concentration of 0.0004-0.0005 M. ) was performed using IXa 3688 (H-D-Leu-Ph'Gly-Arg-AMC; Centerchem).

Factor Xa determinations were performed in 0.1 M sodium phosphate buffer at pH 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000. The crystals were made using purified human factor %)-Gly-Arg-pNA; Chromogenics) was used.

Factor XIIa determinations were performed in 0.05 M HEPES at pH 7.4 containing 0.145 M NaCl, 0.05 M KCl, and 0.1% PEG 8000. The crystals were made using purified human factor -Arg-pNA.2AcOH; American Diagnostica) was used.

Plasma kallikrein determinations were performed in 0.1 M sodium phosphate buffer at pH 7.5 containing 0.1-0.2 M sodium chloride and 0.5% PEG 8000. The determination was performed on purified human plasma kallikrein (Enzyme Research Laboratories) at a final assay concentration of 200 pM and the synthetic substrate S-2302 (H-(D)) at a concentration of 0.00008-0.0004 M. -Pro-Phe-Arg-pNA; Chromogenics) was used.

Thrombin determinations were performed in 0.1 M sodium phosphate buffer at pH 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000. The crystals were made using purified human alpha thrombin (Hematologic Technologies or Enzyme Research Laboratories) at a final assay concentration of 200-250 pM and the synthetic substrate S-2366 (pyroGlu-Pro-) at a concentration of 0.0002-0.0004 M. Arg-pNA; chromogenics or anaspec) was used.

The Michaelis constant, K _m , for substrate hydrolysis by each protease was determined at 25°C or 37°C in the absence of inhibitors. The value of K _i was determined by allowing the protease to react in the presence of substrate and inhibitor. The reaction was allowed to proceed for a period of 20-180 minutes (depending on the protease) and the rate (ratio of change in absorbance or fluorescence versus time) was measured. The following relationship was used to calculate K _i values:

(V _max *S)/(K _m +S);

(v _o -v _s )/v _s = I/(K _i (1 + S/K _m )) for a competitive inhibitor with one binding site; or

v _s /v _{o =} A + ((BA)/1 + ((IC ₅₀ /(I) _n ))); and

K _i = IC ₅₀ /(1 + S/K _m ) for competitive inhibitor

here

v _o is the velocity of the control without inhibitor;

v _s is the velocity in the presence of inhibitor;

V _max is the maximum reaction rate;

I is the concentration of inhibitor;

A is the minimum activity remaining (usually fixed at 0);

B is the maximum activity remaining (usually fixed at 1.0);

n is the Hill coefficient, a measure of the number and cooperativity of potential inhibitor binding sites;

IC ₅₀ is the concentration of inhibitor that produces 50% inhibition under assay conditions;

K _i is the dissociation constant of the enzyme:inhibitor complex;

S is the concentration of substrate;

K _m is the Michaelis constant for the substrate.

The selectivity of a compound can be assessed by taking the ratio of the K _i value for the protease of interest to the K _i value for a given protease (i.e., selectivity for FXIa versus protease P = K _i for protease _P /K i for FXIa) there is. Compounds with a selectivity ratio >20 are considered selective.

The effectiveness of compounds of the invention as inhibitors of coagulation can be determined using standard or modified coagulation assays. An increase in plasma clotting time in the presence of an inhibitor is indicative of anticoagulation. Relative clotting time is the clotting time in the presence of an inhibitor divided by the clotting time in the absence of an inhibitor. The results of this assay can be expressed as IC1.5x or IC2x, which is the inhibitor concentration required to increase the clotting time by 1.5-fold or 2-fold, respectively, relative to the clotting time in the absence of the inhibitor. IC1.5x or IC2x is found by linear interpolation from a plot of relative clotting time versus inhibitor concentration, using the inhibitor concentration encompassing IC1.5x or IC2x.

Clotting times are determined using citrated normal human plasma as well as plasma obtained from a number of laboratory animal species (e.g., rats or rabbits). Compounds are diluted in plasma starting with 10 mM DMSO stock solutions. The final concentration of DMSO is less than 2%. Plasma coagulation assays are performed on an automated coagulation analyzer (Sysmex, Dade-Behring, IL). Similarly, clotting time can be determined from experimental animal species or humans administered compounds of the invention.

Activated partial thromboplastin time (aPTT) is determined using ACTIN® (Dade-Behring, IL) according to the instructions in the package insert. Plasma (0.05 mL) is warmed to 37°C for 1 minute. Actin® (0.05 mL) is added to the plasma and incubated for an additional 2 to 5 minutes. Calcium chloride (25 mM, 0.05 mL) is added to the reaction to initiate coagulation. Clotting time is the time in seconds from the moment calcium chloride is added until a clot is detected.

Prothrombin time (PT) is determined using thromboplastin (Innovin, Dade-Behring, IL) according to the instructions on the package insert. Plasma (0.05 mL) is warmed to 37°C for 1 minute. Thromboplastin (0.1 mL) is added to the plasma to initiate coagulation. Clotting time is the time in seconds from the moment thromboplastin is added until a clot is detected.

Chymotrypsin determinations were performed in 50 mM HEPES buffer at pH 7.4 containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000 (polyethylene glycol; JT Baker or Fisher Scientific). The crystals were based on purified human chymotrypsin (Calbiochem) at a final concentration of 0.2-2 nM and the synthetic substrate S-2586 (methoxy-succinyl-Arg-Pro-) at a concentration of 0.0005-0.005 M. Tyr-pNA; Chromogenics) was used.

Thrombin determinations were performed in 0.1 M sodium phosphate buffer at pH 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000. The crystals were made using purified human trypsin (Sigma) at a final assay concentration of 0.1-1 nM and the synthetic substrate S-2222 (Bz-Ile-Glu (gamma-OMe, 50%) at a concentration of 0.0005-0.005 M. )-Gly-Arg-pNA; Chromogenics) was used.

The exemplary examples disclosed below were tested in the Factor XIa assay described above and found to have Factor XIa inhibitory activity. A range of factor XIa inhibitory activities (Ki values) of ≤10 μM (10000 nM) was observed.

The exemplary examples disclosed below were tested in the plasma kallikrein assay described above, with some examples having both factor XIa and plasma kallikrein inhibitory activity. Inhibitory activity is reported for examples where plasma kallikrein inhibitory activity was observed with Ki values of ≤ 10 μM (10000 nM).

B. In vivo assay

The effectiveness of the compounds of the invention as antithrombotic agents can be determined using relevant in vivo thrombosis models, including the in vivo electrically-induced carotid artery thrombosis model and the in vivo rabbit arteriovenous shunt thrombosis model.

a. In vivo electrically-induced carotid artery thrombosis (ECAT) model

The rabbit ECAT model described by Wong et al. (J. Pharmacol. Exp. Ther., 295:212-218 (2000)) can be used in this study. Male New Zealand white rabbits were anesthetized with ketamine (50 mg/kg + 50 mg/kg/h IM) and xylazine (10 mg/kg + 10 mg/kg/h IM). These anesthetics are replenished as needed. An electromagnetic flow probe is placed on a section of the isolated carotid artery to monitor blood flow. The test agent or vehicle will be given (iv, ip, sc, or orally) before or after the onset of thrombosis. Drug treatment prior to the onset of thrombosis is used to model the ability of the test agent to prevent and reduce the risk of thrombus formation, whereas administration after onset is used to model its ability to treat existing thrombotic disease. Thrombus formation is induced by electrical stimulation of the carotid artery at 4 mA for 3 min using an external stainless-steel bipolar electrode. Carotid blood flow was measured continuously over 90-minute cycles to monitor thrombus-induced occlusion. Total carotid blood flow over 90 minutes is calculated using the trapezoid rule. The average carotid blood flow over 90 minutes is then determined by converting the total carotid blood flow over 90 minutes into a percentage of the total control carotid blood flow that would result if control blood flow had been maintained continuously for 90 minutes. The ED ₅₀ of a compound (the dose that increases mean carotid blood flow over 90 minutes by 50% of control) was calculated using the Hill sigmoid E _max equation (DeltaGraph; SPSS Inc., Chicago, IL). Use a nonlinear least squares regression program to estimate it.

b. In Vivo Rabbit Arteriovenous (AV) Shunt Thrombosis Model

The rabbit AV shunt model described by Wong, PC et al., J. Pharmacol. Exp. Ther. 292:351-357 (2000) can be used in this study. Male New Zealand white rabbits were anesthetized with ketamine (50 mg/kg + 50 mg/kg/h IM) and xylazine (10 mg/kg + 10 mg/kg/h IM). These anesthetics are replenished as needed. The femoral artery, jugular vein, and femoral vein are isolated and catheterized. A saline-filled AV shunt device is connected between the femoral artery cannula and the femoral vein cannula. The AV shunt device consists of an outer piece of Tygon tubing (length = 8 cm; inner diameter = 7.9 mm) and an inner piece of tubing (length = 2.5 cm; inner diameter = 4.8 mm). The AV shunt also contains an 8-cm-long 2-0 silk thread (Ethicon, Somerville, NJ). Blood flows from the femoral artery through the AV-shunt into the femoral vein. Exposure of the bloodstream to the silk thread induces significant thrombus formation. After 40 minutes, the shunt is removed and the clot-covered silk thread is weighed. The test agent or vehicle will be given (iv, ip, sc, or orally) prior to opening of the AV shunt. The percent inhibition of thrombus formation is determined for each treatment group. ID ₅₀ values (dose that produces 50% inhibition of thrombus formation) are estimated by a nonlinear least squares regression program using the Hill sigmoid E _max equation (Deltagraph; SPSS Inc., Chicago, IL).

The anti-inflammatory effects of these compounds can be demonstrated by the Evans Blue dye extravasation assay using C1-esterase inhibitor deficient mice. In this model, mice are administered a compound of the invention, Evans blue dye is injected through the tail vein, and extravasation of the blue dye is determined by spectrophotometric means from tissue extracts.

For example, the ability of the compounds of the invention to reduce or prevent systemic inflammatory response syndromes, such as those observed during on-pump cardiovascular procedures, can be demonstrated in in vitro perfusion systems or in larger mammals, including dogs and baboons. -Can be tested by pump surgical procedure. Readings for assessing the benefit of the compounds of the invention include, for example, reduced platelet loss, reduced platelet/leukocyte complexes, reduced neutrophil elastase levels in plasma, reduced activation of complement factors, and contact activated protein ( and reduced activation and/or consumption of plasma kallikrein, factor XII, factor XI, high molecular weight kininogen, C1-esterase inhibitor).

The compounds of the invention may also be useful as inhibitors of further serine proteases, especially human thrombin, human plasma kallikrein and human plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions including blood coagulation, fibrinolysis, blood pressure regulation and inflammation, and in wound healing catalyzed by the above-mentioned classes of enzymes. Specifically, the compounds are used as drugs for the treatment of diseases resulting from elevated thrombin activity of the above-mentioned serine proteases, such as myocardial infarction, and as reagents used as anticoagulants when processing blood into plasma for diagnostic and other commercial purposes. It has utility.

V. Pharmaceutical Compositions, Formulations and Combinations

The compounds of the invention can be administered in oral dosage forms such as tablets, capsules (each of which includes sustained-release or delayed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous or intramuscular form, all dosage forms used being well known to those skilled in the pharmaceutical arts. They may be administered alone, but will generally be administered in conjunction with a pharmaceutical carrier selected based on the route of administration selected and standard pharmaceutical practice.

The term “pharmaceutical composition” refers to a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier. “Pharmaceutically acceptable carrier” means, depending on the mode of administration and the nature of the dosage form, a medium generally acceptable in the art for the delivery of biologically active agents to animals, especially mammals, such as adjuvants, excipients or vehicles. , such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricants and dispensing agents. Pharmaceutically acceptable carriers are formulated depending on a number of factors within the understanding of those skilled in the art. These include, but are not limited to: the type and nature of the active agent being formulated; a subject to be administered the agent-containing composition; the intended route of administration of the composition; and targeted therapeutic indications. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. These carriers may contain a number of different ingredients and additives in addition to the active agent, and these additional ingredients may be added for various reasons well known to those skilled in the art, for example, for stabilization of the active agent, binder, etc. included in Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection are found in a variety of readily available sources, such as, for example, Remington's Pharmaceutical Sciences, 18th Edition (1990).

The dosing regimen for the compounds of the invention will, of course, depend on known factors, such as the pharmacodynamic properties of the particular agent and its mode and route of administration. the recipient's species, age, gender, health, medical condition, and weight; nature and severity of symptoms; Types of joint treatment; frequency of treatment; It will vary depending on the route of administration, the patient's renal and liver function, and the desired effect. A physician or veterinarian can determine and prescribe the effective amount of medication needed to prevent, reverse, or arrest the progression of a thromboembolic disorder.

As a general guideline, the daily oral dosage of each active ingredient when used for the indicated efficacy is about 0.001 to about 1000 mg/kg body weight per day, preferably about 0.01 to about 100 mg/kg body weight per day; Most preferably it will range from about 0.1 to about 20 mg/kg/day. Intravenously, the most preferred dosage would range from about 0.001 to about 10 mg/kg/min during constant rate infusion. The compounds of the invention may be administered in a single daily dose, or may be administered in divided doses of 2, 3 or 4 times per day for a total daily dose.

Compounds of the invention can also be administered parenterally (eg, intravenously, intraarterially, intramuscularly, or subcutaneously). When administered intravenously or intraarterially, doses may be given continuously or intermittently. Moreover, formulations can be developed for intramuscular and subcutaneous delivery, ensuring gradual release of the active pharmaceutical ingredient. In one embodiment, the pharmaceutical composition is a solid preparation, e.g., a spray-dried composition, which may be used as such or may have solvents and/or diluents added prior to use by the physician or patient.

The compounds of the invention can be administered in intranasal form through topical use of a suitable intranasal vehicle, or via the transdermal route using a transdermal skin patch. When administered in the form of a transdermal delivery system, dose administration will, of course, be continuous rather than intermittent throughout the dosing regimen.

The compounds may be prepared in suitable pharmaceutical diluents, excipients or carriers suitably selected for the intended dosage forms, such as oral tablets, capsules, elixirs and syrups, and consistent with conventional pharmaceutical practice (collectively referred to herein as pharmaceutical carriers). It is typically administered as a mixture with

For example, for oral administration in the form of tablets or capsules, the active drug ingredient may be packaged in an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, phosphoric acid. Can be combined with dicalcium, calcium sulfate, mannitol, sorbitol, etc.; For oral administration in liquid form, the oral drug component can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc. Moreover, if desired or necessary, suitable binders, lubricants, disintegrants and colorants may also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the invention can also be administered in the form of liposomal delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

Compounds of the invention can also be coupled to soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl moieties. Moreover, the compounds of the present invention are a type of biodegradable polymer useful for achieving controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxy It can be coupled with cross-linked or amphiphilic block copolymers of butyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacylates, and hydrogels. Solid dispersions are also called solid-state dispersions. In some embodiments, any of the compounds described herein are formulated as spray dried dispersions (SDDs). SDD is a single-phase amorphous molecular dispersion of a drug in a polymer matrix. It is a solid solution prepared by dissolving the drug and polymer in a solvent (e.g., acetone, methanol, etc.) and spray drying the solution. The solvent rapidly evaporates from the droplet, rapidly solidifying the polymer and drug mixture, trapping the drug in amorphous form as an amorphous molecular dispersion.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 1000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will typically be present in an amount of about 0.1-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and a powdered carrier such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Compressed tablets can be prepared using similar diluents. Both tablets and capsules can be manufactured as sustained release products to provide continuous release of the medication over a period of time. Compressed tablets may be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric-coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain colorants and flavoring agents to increase patient compliance.

In general, water, suitable oils, saline, aqueous dextrose (glucose) and related sugar solutions, and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain water-soluble salts of the active ingredient, suitable stabilizers, and, if necessary, buffering substances. Antioxidants, alone or in combination, such as sodium bisulfite, sodium sulfite or ascorbic acid, are suitable stabilizers. Citric acid and its salts and sodium EDTA are also used. Additionally, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in the standard reference work in the field, Remington's Pharmaceutical Sciences, Mack Publishing Company.

When a compound of the invention is combined with another anticoagulant, for example, the daily dosage may be from about 0.1 to about 100 milligrams of the compound of the invention, and from about 0.1 to about 100 milligrams per kilogram of patient body weight. For tablet dosage forms, the compound of the invention may generally be present in an amount of about 5 to about 300 milligrams per dosage unit, and the second anticoagulant may be present in an amount of about 1 to about 500 milligrams per dosage unit.

As a general guideline, when a compound of the invention is administered in combination with an antiplatelet agent, the typical daily dosage is about 0.01 to about 300 milligrams of the compound of the invention and about 50 to about 150 milligrams of the antiplatelet agent per kilogram of body weight of the patient; Preferably, it may be about 0.1 to about 4 milligrams of the compound of the present invention and about 1 to about 3 milligrams of the antiplatelet agent.

When a compound of the invention is administered in combination with a thrombolytic agent, a typical daily dosage may be from about 0.1 to about 100 milligrams of the compound of the invention per kilogram of patient body weight, and in the case of a thrombolytic agent, when administered alone. The typical dosage of a thrombolytic agent can be reduced by about 50-80% when administered in combination with a compound of the present invention.

The potential for chemical interactions between the combined active ingredients exists, especially when provided in a single dosage unit. For this reason, when a compound of the invention and a second therapeutic agent are combined in a single dosage unit, they are formulated so that physical contact between the active ingredients is minimized (i.e., reduced), even though the active ingredients are combined in a single dosage unit. For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize contact between the combined active ingredients, but also to promote the release of one of these ingredients in the gastrointestinal tract such that one of these ingredients is not released in the stomach but rather in the intestines. It is possible to control it. Additionally, one of the active ingredients may be coated with a material that affects sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Additionally, sustained-release components may be additionally enteric coated so that release of the component occurs only in the intestine. Another approach is to further isolate the active ingredients, in which one component is coated with a sustained-release and/or enteric-release polymer, and the other component is also coated with a polymer such as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC). or coated with other suitable materials as known in the art. The polymer coating serves to form an additional barrier to interaction with other ingredients.

These as well as other ways of minimizing contact between the components of the combination product of the invention, whether administered in a single dosage form or in separate forms but in the same manner and at the same time, will be appreciated by those skilled in the art. It will be readily apparent to

In another embodiment, the invention provides a potassium channel opener, potassium channel blocker, calcium channel blocker, sodium hydrogen exchange channel inhibitor, antiarrhythmic agent, antiatherosclerotic agent, anticoagulant, antithrombotic agent, thrombolytic agent, fibrinogen antagonist, diuretic. , antihypertensive agents, ATPase inhibitors, mineralocorticoid receptor antagonists, phosphodiesterase inhibitors, antidiabetic agents, anti-inflammatory agents, antioxidants, angiogenesis regulators, anti-osteoporosis agents, hormone replacement therapy, hormone receptor modulators, oral contraceptives, anti-obesity. agents, antidepressants, anti-anxiety agents, antipsychotics, antiproliferative agents, antitumor agents, antiulcer agents and gastroesophageal reflux disease agents, growth hormone agents and/or growth hormone secretagogues, thyroid mimetics, anti-infective agents, antiviral agents, A pharmaceutical composition further comprising additional therapeutic agent(s) selected from antibacterial agents, antifungal agents, cholesterol/lipid lowering agents and lipid profile therapy, and agents that mimic ischemic preconditioning and/or myocardial stunning, or combinations thereof. to provide.

In another embodiment, the invention provides an additional agent selected from an antiarrhythmic agent, an antihypertensive agent, an anticoagulant, an antiplatelet agent, a thrombin inhibitor, a thrombolytic agent, a fibrinolytic agent, a calcium channel blocker, a potassium channel blocker, a cholesterol/lipid lowering agent, or a combination thereof. Pharmaceutical compositions are provided that further comprise therapeutic agent(s).

In another embodiment, the invention provides a treatment for warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatroban, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, Dip Ridamole, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, melagatran, ximelagatran, disulfatohirudin, tissue plasmino A pharmaceutical composition is provided, further comprising additional therapeutic agent(s) selected from a gene activator, modified tissue plasminogen activator, anistreplase, urokinase and streptokinase, or combinations thereof.

In another embodiment, the invention provides that the additional therapeutic agent is an ACE inhibitor, AT-1 receptor antagonist, beta-adrenergic receptor antagonist, ETA receptor antagonist, dual ETA/AT-1 receptor antagonist, renin inhibitor (aliskerin) and vaso Antihypertensive agents selected from peptidase inhibitors, antiarrhythmic agents selected from I _Kur inhibitors, thrombin inhibitors, antithrombin-III activators, heparin co-factor II activators, other factor XIa inhibitors, other kallikrein inhibitors, plasminogen activators. Inhibitor (PAI-1) antagonist, thrombin activatable fibrinolysis inhibitor (TAFI) inhibitor, anticoagulant selected from factor VIIa inhibitor, factor IXa inhibitor and factor Xa inhibitor, or GPIIb/IIIa blocker, GP Ib/IX blocker, protease activated receptor 1 (PAR-1) antagonist, protease activated receptor 4 (PAR-4) antagonist, prostaglandin E2 receptor EP3 antagonist, collagen receptor antagonist, phosphodiesterase-III inhibitor, P2Y ₁ receptor antagonist, P2Y ₁₂ antagonist, thromboxane receptor antagonist , a cyclooxygenase-1 inhibitor, and an antiplatelet agent selected from aspirin, or a combination thereof.

In another embodiment, the invention provides pharmaceutical compositions wherein the additional therapeutic agent(s) is an antiplatelet agent or a combination thereof.

In another embodiment, the invention provides a pharmaceutical composition wherein the additional therapeutic agent is the antiplatelet agent clopidogrel.

Compounds of the invention may be administered alone or in combination with one or more additional therapeutic agents. “Administered in combination” or “combination therapy” means that a compound of the invention and one or more additional therapeutic agents are administered jointly to the mammal being treated. When administered in combination, each component may be administered sequentially in any order, either at the same time or at different times. Accordingly, each component can be administered individually, but within sufficiently close proximity to provide the desired therapeutic effect.

Compounds that can be administered in combination with the compounds of the present invention include, but are not limited to, anticoagulants, antithrombin agents, antiplatelet agents, fibrinolytics, lipid lowering agents, antihypertensive agents, and antiischemic agents.

Other anticoagulants (or coagulation inhibitors) that may be used in combination with the compounds of the invention include warfarin, heparin (unfractionated heparin or any commercially available low molecular weight heparin, e.g., LOVEVENOX®), synthetic pentasacca Direct-acting thrombin inhibitors, including ride, hirudin, and argatroban, as well as other factor VIIa inhibitors, factor IXa inhibitors, factor Xa inhibitors known in the art (e.g., ARIXTRA®, Pixaban, rivaroxaban, LY-517717, DU-176b, DX-9065a, and those disclosed in WO 98/57951, WO 03/026652, WO 01/047919, and WO 00/076970), factor XIa inhibitors, and Includes inhibitors of activating TAFI and PAI-1.

As used herein, the term antiplatelet agent (or platelet inhibitor) refers to an agent that inhibits platelet function, for example, by inhibiting platelet aggregation, adhesion, or secretion of granule-containing substances. These agents include a variety of known non-steroidal anti-inflammatory drugs (NSAIDs) such as acetaminophen, aspirin, codeine, diclofenac, droxicam, fentanyl, ibuprofen, indomethacin, ketorolac, mefenamate, morphine, naproxen, and fenamate. Includes, but is not limited to, cetin, piroxicam, sufentanil, sulfinpyrazone, sulindac, and pharmaceutically acceptable salts or prodrugs thereof. Among NSAIDs, aspirin (acetylsalicylic acid or ASA) and piroxicam are preferred. Other suitable platelet inhibitors include glycoprotein IIb/IIIa antagonists (e.g., tirofiban, eptifibatide, abciximab, and integrelin), thromboxane-A2-receptor antagonists (e.g., ifetroban), Thromboxane-A-synthetase inhibitors, phosphodiesterase-III (PDE-III) inhibitors (e.g., dipyridamole, cilostazol) and PDE-V inhibitors (e.g., sildenafil), protease-activated receptor 1 (PAR-1) antagonists (e.g., E-5555, SCH-530348, SCH-203099, SCH-529153 and SCH-205831), and pharmaceutically acceptable salts or prodrugs thereof.

Other examples of antiplatelet agents suitable for use in combination with the compounds of the invention in the presence or absence of aspirin are ADP (adenosine diphosphate) receptor antagonists, preferably antagonists of the purinergic receptors P2Y ₁ and P2Y ₁₂ , where P2Y ₁₂ is It is more desirable than Preferred P2Y ₁₂ receptor antagonists include clopidogrel, ticlopidine, prasugrel, ticagrelor and cangrelor, and pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine and clopidogrel are also preferred compounds as they are known to be milder than aspirin when used in the gastrointestinal tract. Clopidogrel is a more preferred agent.

A preferred example is a triple combination of a compound of the invention, aspirin and another antiplatelet agent. Preferably, the antiplatelet agent is clopidogrel or prasugrel, more preferably clopidogrel.

As used herein, the term thrombin inhibitor (or antithrombin agent) refers to an inhibitor of the serine protease thrombin. By inhibiting thrombin, it interferes with various thrombin-mediated processes, such as thrombin-mediated platelet activation (i.e., aggregation of platelets and/or secretion of platelet granule contents containing serotonin) and/or fibrin formation. A number of thrombin inhibitors are known to those skilled in the art, and these inhibitors are contemplated for use in combination with the compounds of the present invention. These inhibitors include boroarginine derivatives, boropeptides, heparin, hirudin, argatroban, dabigatran, AZD-0837, and those disclosed in WO 98/37075 and WO 02/044145, and pharmaceutically acceptable salts thereof, and Including, but not limited to, prodrugs. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acids, such as lysine, ornithine, arginine, C-terminal a-aminoboronic acid derivatives of homoarginine, and their corresponding isothiouronium analogs. . As used herein, the term hirudin includes suitable derivatives or analogs of hirudin, such as disulfatohirudin, referred to herein as hirulogs.

As used herein, the term thrombolytic agent (or fibrinolytic agent) (or thrombolytic agent or fibrinolytic agent) refers to an agent that dissolves blood clots (thrombus). These agents include tissue plasminogen activator (TPA, natural or recombinant) and its modified forms, anistreplase, urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factor VIIa inhibitor, thrombin inhibitor, inhibitor of factors IXa, Includes soylated plasminogen streptokinase activator complex (including pharmaceutically acceptable salts or prodrugs thereof). As used herein, the term anistreplase refers to the anisoylated plasminogen streptokinase activator complex, for example, as described in European Patent Application No. 028,489, the disclosure of which is incorporated herein by reference. As used herein, the term urokinase is intended to refer to both double and single chain urokinase, the latter also referred to herein as prourokinase.

Examples of cholesterol/lipid lowering agents and lipid profile therapies suitable for use in combination with the compounds of the invention include HMG-CoA reductase inhibitors (e.g., pravastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, and other statins), low-density lipoprotein (LDL) receptor activity modulators (e.g. HOE-402, PCSK9 inhibitors), bile acid sequestrants (e.g. cholestyramine and colestipol), nicotinic acid or its derivatives (e.g. , NIASPAN®), GPR109B (nicotinic acid receptor) modulators, fenofibric acid derivatives (e.g. gemfibrozil, clofibrate, fenofibrate and benzafibrate) and other peroxisome proliferator-activated receptors ( PPAR) alpha modulators, PPARdelta modulators (e.g. GW-501516), PPARgamma modulators (e.g. rosiglitazone), with multiple functional groups to modulate the activity of various combinations of PPARalpha, PPARgamma and PPARdelta. Compounds, probucol or derivatives thereof (e.g. AGI-1067), cholesterol absorption inhibitors and/or Niemann-Pick C1-like transporter inhibitors (e.g. ezetimibe), cholesterol ester transfer protein inhibitors (e.g. For example, CP-529414), squalene synthase inhibitor and/or squalene epoxidase inhibitor or mixtures thereof, acyl coenzyme A: cholesteryl acyltransferase (ACAT) 1 inhibitor, ACAT2 inhibitor, dual ACAT1/2 inhibitor, ileal bile acid transport inhibitors (or apical sodium co-dependent bile acid transport inhibitors), microsomal triglyceride transfer protein inhibitors, liver-X-receptor (LXR) alpha modulators, LXR beta modulators, LXR dual alpha/beta modulators, FXR modulators, omega-3 fatty acids (e.g. For example, 3-PUFA), plant stanols and/or fatty acid esters of plant stanols (e.g., sitostanol esters used in BENECOL® margarine), endothelial lipase inhibitors, and reverse cholesterol transport. and HDL functional mimics that activate (e.g., apoAI derivatives or apoAI peptide mimetics).

The compounds of the invention can be combined with guanylate cyclase inhibitors, chymase inhibitors, ROMK inhibitors, ACE inhibitors, ATII inhibitors, ATR inhibitors, NEP inhibitors and other compounds to treat heart failure.

The compounds of the invention are also useful as standard or reference compounds, for example as quality standards or controls, in tests or assays involving inhibition of thrombin, factor VIIa, IXa, Xa, XIa and/or plasma kallikrein. These compounds can be provided in commercial kits for use in pharmaceutical studies involving, for example, thrombin, factor VIIa, IXa, Xa, XIa, and/or plasma kallikrein. XIa. For example, a compound of the invention can be used as a reference in an assay to compare its known activity to a compound with unknown activity. This will ensure that the experimenter performed the assay properly and will provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the invention can be used to test their effectiveness.

Compounds of the invention may also be used in diagnostic assays involving thrombin, factor VIIa, IXa, Xa, XIa and/or plasma kallikrein. For example, the presence of thrombin, factor VIIa, IXa, It can be determined by adding to a series of solutions containing one species. It will be concluded that Factor

Highly potent and selective compounds of the present invention with K _i values of less than 0.001 μM for the target protease and more than 0.1 μM for other proteases also inhibit thrombin, factors VIIa, IXa, Xa, XIa and/or plasma kallikrein in serum samples. It can be used in diagnostic tests involving quantification of . For example, the amount of Factor XIa in a serum sample can be determined by careful titration of protease activity with a potent Factor

The invention also encompasses articles of manufacture. As used herein, articles of manufacture are intended to include, but are not limited to, kits and packages. The article of manufacture of the present invention includes (a) a first container; (b) a pharmaceutical composition positioned in a first container, comprising a first therapeutic agent comprising a compound of the invention or a pharmaceutically acceptable salt form thereof; and (c) a package insert specifying that the pharmaceutical composition can be used to treat a thromboembolic and/or inflammatory disorder (as defined above). In another embodiment, the package insert specifies that the combination (as defined above) can be used in combination with a second therapeutic agent to treat a thromboembolic and/or inflammatory disorder. The article of manufacture may further comprise (d) a second container, where components (a) and (b) are located within the second container and component (c) is located within or outside the second container. Located within first and second containers means that each container holds articles within its boundaries.

The first container is a receptacle used to hold the pharmaceutical composition. These containers may be for manufacturing, storage, transportation and/or individual/bulk sale. The first container is intended to encompass a bottle, jar, vial, flask, syringe, tube (e.g., for cream formulations) or any other container used in the manufacture, holding, storage or dispensing of pharmaceutical products.

The second container is used to hold the first container and optionally the package insert. Examples of secondary containers include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sachets. The package insert may be physically attached to the outside of the first container via tape, adhesive, staples, or another attachment method, or it may be located inside the second container without any means of physical attachment to the first container. there is. Alternatively, the package insert is located external to the second container. When located outside the second container, it is preferred to physically attach the package insert via tape, adhesive, staples, or another attachment method. Alternatively, it may be adjacent to or in contact with the exterior of the second container without being physically attached to it.

A package insert is a label, tag, marker, etc. that contains information about the pharmaceutical composition placed within the first container. The information presented will typically be determined by the regulatory agency (e.g., U.S. Food and Drug Administration) having jurisdiction over the jurisdiction in which the manufactured product is sold. Preferably, the package insert specifically states that the pharmaceutical composition has been approved. Package inserts may be made of any material that allows a human to read the information contained therein or on them. Preferably, the package insert is a printable material (e.g. paper, plastic, cardboard, foil, self-adhesive backing paper or plastic, etc.) on which the destination information has been formed (e.g. printed or applied). am.

Other features of the invention will become apparent from the following description of exemplary embodiments, which are given for illustrative purposes and are not intended to limit the invention. The following examples have been prepared, isolated, and characterized using the methods disclosed herein.

VI. General synthesis including reaction schemes

The compounds of the present invention can be synthesized by a number of methods available to those skilled in the art of organic chemistry (Maffrand, J.P. et al., Heterocycles, 16(1):35-37 (1981)). The general synthetic schemes for preparing the compounds of the present invention are described below. These schemes are illustrative and are not intended to limit the possible techniques that a person skilled in the art may use to prepare the compounds disclosed herein. Different methods for preparing the compounds of the present invention will be apparent to those skilled in the art. Additionally, the various steps in the synthesis may be performed in alternative orders to obtain the desired compound or compounds.

Examples of compounds of the invention prepared by the methods described in the general schemes are given in the Intermediates and Examples sections that follow. Preparation of homochiral examples can be performed by techniques known to those skilled in the art. For example, homochiral compounds can be prepared by separation of the racemic product by chiral phase preparative HPLC. Alternatively, example compounds can be prepared by methods known to yield enantiomerically enriched products. This includes, but is not limited to, the incorporation of a chiral auxiliary functional group into the racemic intermediate that functions to control the diastereoselectivity of the transformation to provide an enantiomerically enriched product upon cleavage of the chiral auxiliary group.

The compounds of the present invention can be prepared in a number of ways known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below in conjunction with synthetic methods known in the art of synthetic organic chemistry, or by modifications thereto as recognized by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture appropriate for the reagents and materials used and suitable for the transformation to be carried out. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule must be consistent with the proposed transformation. This will sometimes require judgment to modify the sequence of synthetic steps or to select one particular method scheme over another to obtain the desired compound of the invention.

It will also be appreciated that another key consideration in the planning of any synthetic route in this field is the careful selection of protecting groups used to protect the reactive functional groups present in the compounds described in the present invention. An authoritative manual explaining a number of alternatives to the skilled practitioner is Greene et al. (Protective Groups in Organic Synthesis, Fourth Edition, Wiley-Interscience (2006)).

Representative pyrimidinone compound 1a of the present invention can be prepared as described in Scheme 1. Using the procedure described by Xiao (Organic Letters, 11:1421 (2009)) with modifications, the suitably substituted pyrimidin-4-ol derivative 1b is purified in a solvent such as CH ₃ CN in the presence of HATU and DBU. Among them, it can be coupled with an appropriately substituted macrocycle amine 1c to provide pyrimidinone compound 1a. When ring A is a SEM-protected imidazole ring, an additional deprotection step using 4N HCl in dioxane or TFA in DCM is used to provide the compounds of the invention.

<Scheme 1>

Scheme 2 describes the synthesis of suitably substituted pyrimidin-4-ol derivative 1b. 6-Chloropyrimidin-4-ol (2a) using precatalysts such as Pd(PPh ₃ ) ₄ or second generation XPhos in solvent mixtures such as toluene and ethanol or THF in the presence of Hunig's base or tribasic potassium phosphate Suzuki-Miyaura coupling between and an appropriately substituted heteroaryl boronic acid or ester 2c provides 1b. Alternatively, if 4-chloro-6-methoxypyrimidine 2b is used, an additional deprotection step using aqueous HBr at elevated temperature is required to provide pyrimidin-4-ol derivative 1b.

<Scheme 2>

Intermediates for the preparation of compounds of the invention where rings A and B are 6-membered heterocyclyls (e.g. pyridine) can be derived from appropriately substituted aldehydes 3a according to the general method outlined in Scheme 3. Aldehyde 3a ( Condensation of (S)-2-methylpropane-2-sulfinamide gives sulfinimine 3b (Ellman, J., J. Org. Chem., 64:1278 (1999)). Using a modified procedure described by Kuduk (Tetrahedron Letters, 45:6641 (2004)), a suitably substituted Grignard reagent, such as allylmagnesium bromide, is added to sulfinimine 3b to give sulfinamide 3c. Provided as a mixture of diastereomers, which can be separated at various stages of the sequence. Diastereoselectivity for the addition of allylmagnesium bromide to sulfinimine 3b was performed using indium(III) chloride according to a modified procedure of Xu (Xu, MH, Organic Letters, 10(6):1259 (2008)). This can be improved. 4-Chloropyridine 3c and an appropriately substituted heteroaryl boronic acid or ester 3e are reacted with a precatalyst such as Pd(dppf)Cl ₂ in the presence of a base such as potassium phosphate, in a solvent mixture such as DMSO and H ₂ O, or DMF. Suzuki-Miyaura coupling using the CH ₂ Cl ₂ complex gives 3 g. Alternatively, Suzuki-Miyaura coupling between boronic acid 3d and appropriately substituted heteroaryl halide 3f can be used to prepare 3g. Protecting group interconversion can be accomplished in two steps to give 3h. Alternatively, protecting group interconversion may occur first in 3c, followed by Suzuki-Miyaura coupling. Aniline 3h can then be coupled with an appropriately substituted carboxylic acid 3i using a base such as T3P® and pyridine to give amide 3j. Using a modified procedure described by Lovely (Tetrahedron Letters, 44:1379 (2003)), 3j is pretreated with p-toluenesulfonic acid to form pyridinium ions, followed by Cyclization can be done via ring-closing metathesis at elevated temperature in a suitable solvent such as DCM, DCE, or toluene using a catalyst to give the pyridine-containing macrocycle 3k. Alkenes can be reduced with hydrogen on palladium on carbon or platinum oxide and subsequent deprotection with TFA in DCM or 4M HCl in dioxane to give the amine 3l. Compounds of formula 3l can be converted to compounds of the present invention according to Scheme 1.

<Scheme 3>

Methods for synthesizing a wide variety of substituted pyridine compounds useful as starting materials for preparing the compounds of the present invention are well known in the art and have been extensively reviewed. (For examples of useful methods for preparing pyridine starting materials, see Kroehnke, F., Synthesis, 1 (1976); Abramovitch, R.A., ed., "Pyridine and Its Derivatives", The Chemistry of Heterocyclic Compounds, 14 (Suppl. 1-4), John Wiley & Sons, New York (1974); Boulton, A.J. et al., eds., Comprehensive Heterocyclic Chemistry, 2:165-524, Pergamon Press, New York (1984); McKillop, A., ed., Comprehensive Heterocyclic Chemistry, 5:1-300, Pergamon Press, New York (1996)).

In cases where suitably substituted boronic acids are not commercially available, heteroaryl halides are used in palladium-mediated coupling with diborone species such as bis(pinacolato)diborone or bis(neopentyl glycolate)diborone. A variation on this approach was adopted to obtain the corresponding , 5,5-tetramethyl-[1,3,2]dioxaborolane or 5,5-dimethyl-[1,3,2]dioxaborolane intermediate can be obtained. Alternatively, this same intermediate can be reacted with the intermediate halide and the corresponding dialcoholoxyhydroborane as described by Murata et al. (J. Org. Chem., 62(19):6458-6459 (1997)). It can be manufactured by. The boron pinacholate intermediate can be used in place of the boronic acid for coupling to aryl/heteroaryl halides or triflates or the boron pinacholate intermediate can be converted to the boronic acid. Alternatively, the corresponding boronic acid can be prepared by metal-halogen exchange of an aryl/heteroaryl halide, quenching with a trialkoxyborate reagent, and aqueous work-up to provide the boronic acid (Miyaura, N. et al. , Chem. Rev., 95:2457 (1995)).

Additionally, the scope of intermediate synthesis is covered by Suzuki since the precursor heteroaryl halides or triflates described above are also precursors for Stille, Negishi, Hiyama, and Kumada-type cross-coupling methodologies. -It is recognized that further expansions can be made beyond the use of the Miyaura coupling methodology (Tsuji, J., Transition Metal Reagents and Catalysts: Innovations in Organic Synthesis, John Wiley & Sons (2000); Tsuji, J., Palladium Reagents and Catalysts: Innovations in Organic Synthesis, John Wiley & Sons (1996)).

Intermediates for the preparation of compounds of the invention wherein ring A is an imidazole ring can be prepared from appropriately N-protected allylglycine (4a) according to the general method outlined in Scheme 4 (Contour-Galcera et al., Bioorg. Med. Chem. Lett., 11(5):741-745 (2001)). Condensation of 4a and a suitably substituted alpha-bromo-ketone (4b) bearing a heteroaryl group in the presence of a suitable base such as potassium bicarbonate, potassium carbonate or cesium carbonate in a suitable solvent such as DMF provides the keto ester intermediate, which Cyclization can be done by heating in a solvent such as toluene or xylene in the presence of excess ammonium acetate to give imidazole (4c). This latter transformation can conveniently be carried out on a small scale in a microwave reactor at 160° C. or on a larger scale with the mixture refluxed while the water is removed via a Dean-Stark trap. The resulting imidazole intermediate (4c) is then protected by treatment with SEM-Cl in a solvent such as THF or DCM in the presence of a base such as sodium hydride or dicyclohexylmethylamine. The resulting heteroaryl bromide (4d) was then reacted with the corresponding amino-heterocyclyl (4e) by heating with excess ammonium hydroxide in a sealed vessel in DMSO as solvent in the presence of copper iodide, a base such as potassium carbonate and a catalytic amount of proline. ) is converted to Acylation of 4e with a suitable alkenoic acid and a coupling agent such as T3P® or BOP reagent, or alternatively, treatment with an alkenoic acid chloride in the presence of a base such as TEA or DIPEA, or pyridine, provides diene 4f, which can be prepared in dilute solution. ring-closing metathesis by heating in a suitable solvent such as DCM or DCE in the presence of p-toluene sulfonic acid and a second generation Grubbs catalyst to give the corresponding macrocycle (4g). Alternatively, RCM can be run without pTsOH at elevated temperature in the microwave. Reduction of the double bond followed by bromination with NBS at room temperature gives 4 h. Suzuki-Miyaura coupling with methylboronic acid or tetramethylstannane and removal of the protecting group (PG) provides intermediate 4i. Intermediate 4i can be converted to the compounds of the invention following the steps described in Scheme 1.

<Scheme 4>

Scheme 5 describes intermediates in the invention where ring B is heterocyclyl (eg -pyrazole). Chloropyridine 3b provides 5a through protecting group interconversion, which is described in Sames (Goikhman, R., Jacques, TL and Sames, D., J. Am. Chem. Soc., 131:3042 (2009) ) can be coupled to 4-nitropyrazole 5b upon heating with a Pd(II) salt such as Pd(OAc) ₂ in a solvent such as DMF or DMA in the presence of a phosphine ligand and a base such as calcium carbonate. Zinc/HOAc reduction of nitropyrazole, 5c, followed by amidation with an appropriately substituted carboxylic acid, 5d, affords 5e. Macrocyclization is then achieved via ring-closing metathesis using Grubbs' second generation ruthenium catalyst to give 5f. Hydrogenation and protecting group cleavage of the resulting olefin gave 5 g of amine. Compounds of formula 5g can be converted to compounds of the present invention upon coupling with an appropriately substituted pyrimidin-4-ol derivative, 1b, according to Scheme 1.

<Scheme 5>

Compounds of the invention bearing alternative regiochemical pyrazole substitutions can be synthesized as shown in Scheme 6. When R is a suitable protecting group (e.g. -trimethylsilylethoxymethyl), deprotection of 6a to 6b followed by alkylation with an alkyl halide under basic conditions, in the presence of a Cu(II) salt such as Cu(OAc) ₂ This can be followed by reaction with boronic acid, or with aryl iodide in the presence of CuI and a diamine ligand. In most cases, alkylation proceeds to give only the products shown in 6c. In optional cases, products with the pyrazole regiochemistry shown in Scheme 5 are formed as minor components.

Compounds of the invention bearing alternative regiochemical pyrazole substitutions can be synthesized as shown in Scheme 6. When R is a suitable protecting group (e.g. -trimethylsilylethoxymethyl), deprotection of 6a to 6b followed by alkylation with an alkyl halide under basic conditions, in the presence of a Cu(II) salt such as Cu(OAc) ₂ This can be followed by reaction with boronic acid, or with aryl iodide in the presence of CuI and a diamine ligand. In most cases, alkylation proceeds to give only the products shown in 6c. In optional cases, products with the pyrazole regiochemistry shown in Scheme 5 are formed as minor components.

<Scheme 6>

Intermediates for the preparation of compounds of the present invention where R ^1a is -F can be prepared according to Scheme 7. Olefin 5f can be applied to hydrofluorination to provide as much as four isomeric alkyl fluorides. Separation of the isomers followed by deprotection of the amine protecting group is achieved by the action of TFA or HCl as shown above in Scheme 3-5. Intermediates 7a and 7b can be elaborated into compounds of the invention according to the procedure described in Scheme 1.

<Scheme 7>

Intermediates for the preparation of compounds of the invention corresponding to formula V can be prepared according to Scheme 8. Chloropyridine 5a reacts with aqueous hydrazine to produce substituted hydrazine 8a. This hydrazine can be cyclized upon treatment with α-cyanoketone 8b to give aminopyrazole 8c. These intermediates (8c) can be elaborated into compounds of the invention according to the procedures described in Schemes 1 and 3.

<Scheme 8>

Scheme 9 describes the synthesis of suitably substituted pyrimidin-4-ol derivatives where G ¹ is substituted phenyl. Aniline 9a can be converted to suitably substituted triazole 9b in a one-pot, two-step sequence. Specifically, aniline 9a is converted in situ to an aryl azide followed by cycloaddition with a suitably substituted alkyne in the presence of a copper catalyst such as Cu ₂ O to provide 9b. Demethylation of 9b according to Scheme 2 gives the pyrimidin-4-ol derivative 9c. When R ¹⁰ is a trimethylsilyl group, the silyl moiety can be converted to chloride at elevated temperature using NCS in the presence of silica gel. Aniline 9a can be converted to iodide 9d using p-TsOH, NaNO ₂ and NaI. Iodide 9d is subjected to various N-arylation or Suzuki-Miyaura coupling followed by demethylation according to Scheme 2 to provide additional pyrimidin-4-ol derivative 9e. When R ⁸ is a tetrazole, intermediate 9g can be prepared by first treatment of aniline 9a with trimethoxymethane and sodium azide followed by demethylation according to Scheme 2.

<Scheme 9>

Scheme 10 describes the synthesis of suitably substituted pyrimidin-4-ol derivatives where R ⁸ is thiadiazole. Bromide 10a can be converted to acetyl compound 10b by coupling 1-(trimethylsilyl)ethanone with a Pd catalyst. 10b can react with ethyl hydrazinecarboxylate to form 10c, which upon treatment with SOCl ₂ gives the thiadiazole compound 10d. Intermediate 10e can be obtained by demethylation of 10d according to Scheme 2.

<Scheme 10>

A representative synthesis of compounds of the invention where ring A is methoxy-pyridone is outlined in Scheme 11. Benzaldehyde 11a and (S)-tert-butyl (1-(dimethoxyphosphoryl)-2-oxohex-5-en-3-yl) used in Horner-Wadsworth-Emmons reaction The carbamate (synthesis described above) provides 11b. Enone 11b was then converted to major intermediate 11c by treatment with NH ₄ OAc and separated into 11d1 and 11d2 by chiral chromatography. Methylation of the chiral separation product 11d2 gives 2-methoxy pyridine 11e. Zn-mediated reduction of the nitro group gives aniline 11f. Coupling of aniline 11f and 2-methylbut-3-enoic acid by methods known in the art of synthesis resulted in the formation of 11g. The following ring-closure metathesis formed two isomers, 11h1 and 11h2. Hydrogenation and deprotection of 11h1 and 11h2 gave crude intermediates 11l1 and 11l2, which can be coupled to give the compounds of the present invention.

<Scheme 11>

Corresponding pyridone compounds of the invention can also be prepared by the methodologies outlined in Schemes 12-14.

<Scheme 12>

<Scheme 13>

<Scheme 14>

Other azole containing compounds of the invention can also be approached by following the procedure outlined for the pyridine/one ring system via the scheme shown in Scheme 15.

<Scheme 15>

Purification of intermediates and final products was performed via normal or reversed phase chromatography. Normal phase chromatography was performed using prepacked SiO ₂ cartridges eluting with a gradient of hexane and EtOAc or DCM and MeOH unless otherwise indicated. Reverse-phase preparative HPLC was performed using a C18 column with a gradient of solvent A (90% water, 10% MeOH, 0.1% TFA) and solvent B (10% water, 90% MeOH, 0.1% TFA, UV 220 nm), or Gradient of solvent A (90% water, 10% ACN, 0.1% TFA) and solvent B (10% water, 90% ACN, 0.1% TFA, UV 220 nm), or solvent A (98% water, 2% ACN, 0.05% TFA) and solvent B (98% ACN, 2% water, 0.05% TFA, UV 220 nm) (or) C18 OBD 5μ 30x100 mm for Sunfire purification, eluting with a 25 min gradient from 0-100% B. I did it as instructed. A = H ₂ O/ACN/TFA 90:10:0.1. B = ACN/ _H2O /TFA 90:10:0.1

Unless otherwise stated, analysis of the final product was performed by reverse phase analytical HPLC.

Method A: Waters SunFire column (3.5 μm C18, 3.0 x 150 mm). A gradient elution (0.5 mL/min) from 10-100% Solvent B over 12 minutes and then 100% Solvent B over 3 minutes was used. Solvent A is (95% water, 5% acetonitrile, 0.05% TFA) and solvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV 254 nm).

Method B: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-μm particles; Mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50℃; Gradient: 0-100% B over 3 min, then 0.75-min hold at 100% B; Flow rate: 1.11 mL/min.

Method C: Waters Acquiti UPLC BEH C18, 2.1 x 50 mm, 1.7-μm particles; Mobile phase A: 5:95 acetonitrile:water (containing 0.1% TFA); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% TFA); Temperature: 50℃; Gradient: 0-100% B over 3 minutes, then 0.75-minute hold at 100% B; Flow rate: 1.11 mL/min

Method X: ZORBAX® SB C18 column (4.6x75mm). A gradient elution (2.5 mL/min) from 0-100% Solvent B over 8 minutes followed by 100% Solvent B over 2 minutes was used. Solvent A is (90% water, 10% MeOH, 0.02% H ₃ PO ₄ ) and solvent B is (10% water, 90% MeOH, 0.02% H ₃ PO ₄ , UV 220 nm).

intermediate 1

Preparation of N-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide

1A. Preparation of N-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide

Et ₃ N (2.1 mL, 15.3 mmol) was dissolved in 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (3 g, 12.7 mmol) and TFAA (2.2 mL, 15.3 mmol) in DCM (100 mL). mmol) was added to the solution. The solution was stirred at room temperature for 1 hour. The solution was then concentrated to a volume of approximately 15 mL and purified by normal phase silica gel chromatography (hexane-EtOAc gradient) to yield N-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl) -2,2,2-Trifluoroacetamide (4 g, 12.06 mmol, 95% yield) was obtained as a white powder.

1B. Preparation of N-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide

N-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoro in HOAc (20 ml) and 48% aqueous HBr (5.5 ml, 48.2 mmol) A clear orange solution of roacetamide (3.2 g, 9.65 mmol) was warmed to 60° C. for 1.5 hours. The reaction was cooled to room temperature and the solvent was removed under vacuum. EtOAc (100 mL) and saturated aqueous NaHCO ₃ were added to the residue. The aqueous layer was then extracted twice with EtOAc (50 mL). The combined organic layers were dried over MgSO ₄ and concentrated. The residue was triturated with Et ₂ O and filtered to obtain N-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide (1.2 g, 3.78 mmol, 39.2% yield) was obtained as a white powder.

intermediate 2

Preparation of (R)-2-methylbut-3-enoic acid

2A. Preparation of (R)-4-benzyl-3-((R)-2-methylbut-3-enoyl)oxazolidin-2-one

To a solution of 2-methylbut-3-enoic acid (5.59 g, 55.9 mmol) and NMM (6.14 mL, 55.9 mmol) in THF (62 mL) at 0° C. was added pivaloyl chloride (6.87 mL, 55.9 mmol) dropwise. . The reaction mixture was cooled to -78°C and stirred for -2 hours. In a separate flask: 2.5 M nBuLi (20.49 mL, 51.2 mmol) in hexane to a solution of (R)-4-benzyloxazolidin-2-one (8.25 g, 46.6 mmol) in THF (126 mL) at -78°C. was added dropwise. After 35 minutes, this reaction was transferred to the first reaction via cannula. The reaction mixture was stirred at -78°C for 2 hours, then the cooling bath was removed and the reaction was quenched with saturated NH ₄ Cl. The reaction was diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a yellow oil (15 g). Purification by silica gel chromatography gave (R)-4-benzyl-3-((R)-2-methylbut-3-enoyl)oxazolidin-2-one (6.59 g, 55%) as a colorless oil. It was obtained as. MS(ESI) m/z: 282.1 (M+Na) ⁺ .

^1H NMR (500 MHz, CDCl ₃ ) ( 7.36 - 7.19 (m, 5H), 6.03 - 5.93 (m, 1H), 5.23 - 5.10 (m, 2H), 4.69 - 4.63 (m, 1H), 4.51 - 4.43 (m, 1H), 4.23 - 4.15 (m, 2H), 3.29 (dd, J = 13.5, 3.3 Hz, 1H), 2.79 (dd, J = 13.5, 9.6 Hz, 1H), 1.35 (d, J = 6.9) Hz, 3H) ppm. Other diastereomers (R)-4-benzyl-3-((S)-2-methylbut-3-enoyl)oxazolidin-2-one (4.6 g, 38%) Also obtained as a white solid MS(ESI) m/z: 260.1 (M+H) ⁺ .

2B. Preparation of (R)-2-methylbut-3-enoic acid

Clear solution of (R)-4-benzyl-3-((R)-2-methylbut-3-enoyl) oxazolidin-2-one (6.05 g, 23.33 mmol) in THF (146 mL) at 0°C. To the colorless solution was added dropwise 30% aqueous H ₂ O ₂ (9.53 mL, 93 mmol) followed by 2 N LiOH (23.33 mL, 46.7 mmol). After 30 minutes, the reaction was quenched with 25 mL of saturated NaHCO ₃ and 25 mL of saturated Na ₂ SO ₃ . The reaction was then concentrated to remove THF. The residue was diluted with water and extracted with CHCl ₃ (3x). The aqueous layer was acidified to pH ~3 using concentrated HCl and then extracted with EtOAc (3x). The EtOAc layers were combined, washed with brine, dried over MgSO ₄ , filtered, and concentrated to give (R)-2-methylbut-3-enoic acid (2.15 g, 92%) as a colorless oil.

^1H NMR (500 MHz, CDCl ₃ ) ( 10.84 (br. s., 1H), 5.94 (ddd, J = 17.4, 10.1, 7.4 Hz, 1H), 5.22 - 5.13 (m, 2H), 3.23 - 3.15 ( m, 1H), 1.31 (d, J = 7.2 Hz, 3H) ppm.

intermediate 3

Preparation of 6-(3-chloro-2-fluorophenyl)pyrimidin-4-ol

6-chloropyrimidin-4-ol (0.100 g, 0.766 mmol), (3-chloro-2-fluorophenyl)boronic acid (0.534 g, 3.06 mmol), and Pd(PPh ₃ ) ₄ (0.089 g, 0.077 mmol) was purged with Ar for several minutes. Degassed toluene (1.53 mL) and EtOH (1.53 mL) were then added, followed by DIEA (0.54 mL, 3.06 mmol). The vial was capped and the reaction was microwaved at 120°C for 1 hour. The resulting clear orange solution was allowed to cool to room temperature and a precipitate formed. The yellow solid was removed by filtration and rinsed with 1:1 toluene/EtOH. A precipitate formed in the filtrate. The yellow solid was removed by filtration, rinsed with cold 1:1 toluene/EtOH, air-dried, and dried under vacuum to give 6-(3-chloro-2-fluorophenyl)pyrimidin-4-ol (0.0357 g). , 21% yield) was obtained as a white solid. MS(ESI) m/z: 225.1 (M+H) ⁺ and 227.1 (M+2+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 12.71 (br. s., 1H), 8.31 (d, J=1.1 Hz, 1H), 7.87 (ddd, J=8.0, 7.2, 1.7 Hz, 1H), 7.74 - 7.69 (m, 1H), 7.36 (td, J=8.0, 1.1 Hz, 1H), 6.72 (br. s, 1H). ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -117.48.

intermediate 4

Preparation of 6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol, hydrobromide

4A. Preparation of 4-(3-chloro-2,6-difluorophenyl)-6-methoxypyrimidine

4-Chloro-6-methoxypyrimidine (1.0 g, 6.92 mmol), (3-chloro-2,6-difluorophenyl)boronic acid (1.996 g, 10.38 mmol), and second generation XPhos precatalyst ( The flask containing 0.272 g, 0.346 mmol) was purged with Ar for a few minutes, then degassed THF (13.84 mL) and degassed 0.5 MK ₃ PO ₄ (27.7 mL, 13.84 mmol) were added. The resulting cloudy, pink reaction mixture was stirred vigorously at room temperature. After 2 hours, the reaction was diluted with water and extracted with EtOAc (2x). The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give an orange-brown residue weighing 1.5 g. Purification by normal phase chromatography gave 4-(3-chloro-2,6-difluorophenyl)-6-methoxypyrimidine (0.242 g, 13.6% yield) as an off-white solid. MS(ESI) m/z: 257.0 (M+H) ⁺ and 259.0 (M+2+H) ⁺ .

¹ H NMR (500 MHz, CD ₃ OD) δ 8.86 (d, J=1.1 Hz, 1H), 7.68 - 7.63 (m, 1H), 7.17 (td, J=9.0, 1.8 Hz, 1H), 7.10 - 7.08 ( m, 1H), 4.07 (s, 3H). ¹⁹ F NMR (471MHz, CD ₃ OD) δ -115.84 (d, J=4.3 Hz), -116.49 (d, J=5.7 Hz).

4B. Preparation of 6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol

A clear solution of 4-(3-chloro-2,6-difluorophenyl)-6-methoxypyrimidine (0.240 g, 0.935 mmol) in AcOH (9.35 mL) and 48% aqueous HBr (5.29 mL, 46.8 mmol) The yellow solution was warmed to 85°C. After 1 hour, the reaction was cooled to room temperature and then concentrated to give a yellow solid. Et ₂ O (10 mL) was added to create a suspension. The solid was collected by filtration, rinsed with Et ₂ O, air-dried, and then dried under vacuum to obtain 6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol (0.258 g, 85% yield) was obtained as an off-white solid. MS(ESI) m/z: 243.0 (M+H) ⁺ and 245.0 (M+2+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 8.33 (d, J=1.1 Hz, 1H), 7.77 (td, J=8.7, 5.6 Hz, 1H), 7.32 (td, J=9.1, 1.7 Hz, 1H ), 6.63 (d, J=0.6 Hz, 1H). ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -113.79 (d, J=4.3 Hz), -113.88 (d, J=5.7 Hz).

intermediate 5

Preparation of 6-(5-chloro-2-fluorophenyl)pyrimidin-4-ol

5A. Preparation of 4-(5-chloro-2-fluorophenyl)-6-methoxypyrimidine

4-Chloro-6-methoxypyrimidine (0.290 g, 2.007 mmol) in DME (10 mL), EtOH (1.250 mL) and water (1.250 mL), (5-chloro-2-fluorophenyl)boronic acid ( A microwave vial containing Na 2 CO ₃ (0.35 g, 2.007 mmol) and Na ₂ CO 3 (0.213 g, 2.007 mmol) was purged with N ₂ for several minutes. PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.082 g, 0.100 mmol) was then added and the vial was capped. The reaction was heated in the microwave at 100°C for 1 hour. The reaction mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with brine and then concentrated to give an orange-brown residue. Purification by normal phase chromatography gave 4-(5-chloro-2-fluorophenyl)-6-methoxypyrimidine (400 mg, 84% yield) as white crystals. MS(ESI) m/z: 239.3 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.86 (s, 1H), 8.16 (dd, J=6.7, 2.8 Hz, 1H), 7.39 (ddd, J=8.8, 4.2, 2.9 Hz, 1H), 7.28 - 7.23 (m, 1H), 7.12 (dd, J=10.8, 8.8 Hz, 1H), 4.04 (s, 3H).

5B. Preparation of 6-(5-chloro-2-fluorophenyl)pyrimidin-4-ol

A clear yellow solution of 4-(5-chloro-2-fluorophenyl)-6-methoxypyrimidine (300 mg, 1.257 mmol) in AcOH (12.57 mL) and 48% aqueous HBr (7 mL, 61.9 mmol) It was heated to 85°C. After 0.5 hours, the reaction was cooled to room temperature and concentrated to dryness under high vacuum. To the residue was carefully added saturated NaHCO ₃ to obtain a suspension. The solid was collected by filtration, rinsed with water, a small amount of acetone, and air dried to give 6-(5-chloro-2-fluorophenyl)pyrimidin-4-ol (140 mg, 36.5% yield) as a white solid. Obtained. MS(ESI) m/z: 225.2 (M+H) ⁺ .

^1H NMR (400MHz, DMSO-d ₆ ) δ 12.73 (br. s., 1H), 8.33 (d, J=0.9 Hz, 1H), 7.99 (dd, J=6.6, 2.9 Hz, 1H), 7.61 ( ddd, J=6.6, 4.3, 2.1 Hz, 1H), 7.43 (dd, J=11.1, 8.9 Hz, 1H), 6.76 (s, 1H).

intermediate 6

Preparation of (S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)

boronic acid

6A. Preparation of 4-chloro-2-[(E)-2-[(S)-2-methylpropane-2-sulfinyl]ethenyl]pyridine

To a solution of S-(-)-t-butyl-sulfinamide (0.856 g, 7.06 mmol) in DCM (14.1 mL) was added sequentially CuSO ₄ (2.481 g, 15.54 mmol) and 4-chloropicolinaldehyde (1.0 g, 7.06 mmol) was added. The resulting white suspension was stirred at room temperature. After 3 hours, the brown suspension was filtered through CELITE® eluting with DCM to give a clear brown filtrate. The filtrate was concentrated to give a brown oil weighing 1.85 g. Purification by normal phase chromatography gave 1.31 g of 4-chloro-2-[(E)-2-[(S)-2-methylpropane-2-sulfinyl]ethenyl]pyridine as a clear yellow oil. MS(ESI) m/z: 245.0 (M+H) ⁺ .

6B. Preparation of (S)-N-((S)-1-(4-chloropyridin-2-yl)but-3-enyl)-2-methylpropane-2-sulfinamide

To a cooled (0 - 5° C.) mixture of InCl ₃ (13.56 g, 61.3 mmol) in THF (170 mL) was added dropwise 1 M allylmagnesium bromide (62 mL, 61.3 mmol) in Et ₂ O over 30 min. The reaction was allowed to warm to room temperature. After 1 h at room temperature, chloro-2-[(E)-2-[(S)-2-methylpropane-2-sulfinyl]ethenyl]pyridine (10 g, 40.9 mmol) in EtOH (170 mL) The solution was added. After 3 hours, the reaction was concentrated under vacuum at 50-55°C. The crude material was partitioned between EtOAc (200 mL) and water (50 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 50 mL). The organic layers were combined, washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give (S)-N-((S)-1-(4-chloropyridin-2-yl) But-3-enyl)-2-methylpropane-2-sulfinamide (13.5 g, 106%) was obtained as a yellow oil. MS(ESI) m/z: 287.2 (M+H) ⁺ .

6C. Preparation of (S)-tert-butyl 1-(4-chloropyridin-2-yl)but-3-enylcarbamate

(S)-N-((S)-1-(4-chloropyridin-2-yl)but-3-enyl)-2-methylpropane-2-sulfinamide (75 g, 261 mmol) was dissolved in MeOH (1500 mL). 6 N aqueous HCl (750 mL, 4.5 mol) was added. The reaction was stirred at room temperature for 3 hours and then concentrated. The residue was diluted with water (2 L) and washed with EtOAc (500 mL). The aqueous layer was basified with saturated Na ₂ CO ₃ solution and then extracted with EtOAc (3 x 1 L). The combined organic layers were washed with water (1 L) and brine (1 L), dried over Na ₂ SO ₄ , filtered and concentrated under vacuum at 50-55° C. to give the crude product (43 g, 90%). did. MS(ESI) m/z: 183.2 (M+H) ⁺ . The crude product (42 g, 230 mmol) was dissolved in DCM (420 mL) and Et ₃ N (32.1 mL, 230 mmol) was added followed by Boc ₂ O (53.4 mL, 230 mmol) dropwise. The reaction was stirred at room temperature for 3 hours. The reaction was diluted with DCM (1 L) and washed with water (500 mL) and brine (500 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was then purified using silica gel chromatography to yield (S)-tert-butyl 1-(4-chloropyridin-2-yl)but-3-enylcarbamate (61 g, 86%). Obtained as a yellow solid. MS(ESI) m/z: 283.2 (M+H) ⁺ .

6D. Preparation of (S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronic acid trifluoroacetate

5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (1.198 g, 5.30) prepared as described in Intermediate 23 in DMSO (10 mL) mmol) and (S)-tert-butyl 1-(4-chloropyridin-2-yl)but-3-enylcarbamate (1.0 g, 3.54 mmol) in KOAc (1.041 g, 10.61 mmol) and PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.289 g, 0.354 mmol) was added. The reaction was purged with Ar for 10 minutes. The reaction mixture was then sealed and stirred at 85°C for 12 hours. The reaction mixture was cooled to room temperature, then it was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purified by reverse phase chromatography to obtain (S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronic acid trifluoroacetate. (1.1 g, 77%) was obtained as a white solid. MS(ESI) m/z: 293.2 (M+H) ⁺ .

^1H NMR (500 MHz, CD ₃ OD) (8.54 (d, J = 5.8 Hz, 1H), 8.11 (s, 1H), 8.02 (dd, J = 5.8, 0.6 Hz, 1H), 5.79 (ddt, J = 17.1, 10.2, 7.1 Hz, 1H), 5.11 - 5.03 (m, 2H), 4.86 (t, J = 7.0 Hz, 1H), 2.69 - 2.55 (m, 2H), 1.40 (br. s., 9H) ppm.

intermediate 7

Preparation of 6-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

7A. Preparation of N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide

To a cooled (-10°C) suspension of 4-chloro-3-fluoroaniline (10.67 g, 73.3 mmol) and Na ₂ CO ₃ (13.21 g, 125 mmol) in Et ₂ O (300 mL) was added TFAA (12.23 mL). , 88 mmol) was added dropwise. The mixture was allowed to warm to room temperature overnight. The mixture was diluted with hexane (300 mL) and filtered. The filtrate was washed with ice water, 10% aqueous NaHCO ₃ , and brine, dried over Na ₂ SO ₄ , filtered, and concentrated to give N-(4-chloro-3-fluorophenyl)-2,2,2- Trifluoroacetamide (17 g, 96% yield) was obtained as a light yellow solid. MS(ESI) m/z: 242.1 (M+H) ⁺ .

7B. Preparation of (3-chloro-2-fluoro-6-(2,2,2-trifluoroacetamido)phenyl)boronic acid

To a cooled (-78°C) clear, colorless solution of N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (0.500 g, 2.070 mmol) in THF (8.28 mL). 2.5 M nBuLi (1.74 mL, 4.35 mmol) in hexane was added dropwise over 15 minutes maintaining the internal temperature below -65°C. The resulting clear yellow solution was stirred at -78°C for 10 minutes. The reaction was allowed to warm to -50°C over 1 hour. The reaction was then cooled to -78°C, and B(Oi-Pr) ₃ (1.051 mL, 4.55 mmol) was added dropwise. The reaction was stirred at -78°C for 30 minutes, then the ice bath was removed, the reaction was allowed to warm to room temperature, and stirred at room temperature for 1 hour. The reaction was then cooled to -5°C and then quenched by dropwise addition of 1.0 M HCl (5 mL) followed by the addition of water (5 mL). The resulting cloudy yellow reaction mixture was stirred at room temperature for 45 minutes. The reaction was diluted with EtOAc and the layers were separated. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a light orange solid. The solid was partitioned between THF (10 mL) and 0.5 M HCl (20 mL) and stirred vigorously for 4 hours. The layers were then separated, and the clear, colorless aqueous layer was concentrated to (3-chloro-2-fluoro-6-(2,2,2-trifluoroacetamido)phenyl)boronic acid (0.1599 g, 34.2%). Yield) was obtained as a white solid. MS(ESI) m/z: 189.9 [M+H] ⁺ .

7C. Preparation of 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline

4-Chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline was purified according to the procedure described in Intermediate 3 (3-chloro-2-fluoro-6-(2,2,2 -Trifluoroacetamido)phenyl)boronic acid was used to prepare it. MS(ESI) m/z: 253.9 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.82 (d, J=1.1 Hz, 1H), 7.18 (dd, J=8.8, 8.3 Hz, 1H), 7.01 (dd, J=3.0, 1.1 Hz, 1H) , 6.61 (dd, J=8.9, 1.5 Hz, 1H), 4.04 (s, 3H). ¹⁹ F NMR (471 MHz, CD ₃ OD) δ -119.92 (s, 1F).

7D. Preparation of 4-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine trifluoroacetate

In a microwave vial, 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (0.045 g, 0.177 mmol) in CH ₃ CN (1.8 mL) cooled to 0°C. Isoamylnitrite (0.036 mL, 0.266 mmol) was added followed by TMSN ₃ (0.035 mL, 0.266 mmol) dropwise. Gas evolution was observed. After 5 minutes, the cooling bath was removed and the reaction was allowed to warm to room temperature. After 1 hour, trimethylsilylacetylene (0.076 mL, 0.532 mmol) was added. The septum was replaced with a microwave stopper and sealed. The reaction was heated in the microwave at 120°C for a total of 4 hours. The reaction product was almost concentrated to dryness and then purified by reverse phase chromatography to obtain 4-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy. Cipyrimidine (27 mg, 0.088 mmol) was obtained as a clear glass. MS(ESI) m/z: 306.3 (M+H) ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 8.74 (d, J=0.4 Hz, 1H), 7.80 (d, J=0.9 Hz, 1H), 7.77 - 7.69 (m, 2H), 7.38 (dd, J=8.6) , 1.5 Hz, 1H), 6.88 (s, 1H), 4.06 (s, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -76.02 (s), -112.27 (s).

7E. Preparation of 6-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

6-(3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol is reacted with 6-(5-chloro-2-fluoro) 4-(5-chloro-2-fluorophenyl)-6-methoxypyrimidine was reacted with 4-(3-chloro-2-fluorophenyl) following the procedure described in Intermediate 5 for the synthesis of phenyl)pyrimidin-4-ol. It was prepared by substituting rho-6-(1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine. MS(ESI) m/z: 292.3 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.20 (d, J=1.1 Hz, 1H), 8.06 (d, J=0.7 Hz, 1H), 7.89 - 7.81 (m, 1H), 7.80 (d, J= 0.9 Hz, 1H), 7.54 (dd, J=8.6, 1.5 Hz, 1H), 6.52 (s, 1H).

intermediate 8

Preparation of 6-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

8A. Preparation of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline

4-Chloro-2-(6-methoxypyrimidin-4-yl)aniline was reacted with (5-chloro-2-fluorophenyl)boronic acid according to the procedure described in Intermediate 5 to 4-chloro-2-(4, It was synthesized by replacing it with 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. MS(ESI) m/z: 236.3 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.78 (s, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.15 (dd, J=8.6, 2.4 Hz, 1H), 6.99 (d, J=0.9) Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 4.02 (s, 3H).

8B. Preparation of 6-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

6-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol was reacted with 6-(3-chloro-2-fluoro-6-(1H 4-chloro-3-fluoro-2-(6-methoxypyrimidine-4) following the procedure described for the synthesis of -1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol -yl)aniline was synthesized by replacing 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline. MS(ESI) m/z: 274.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.51 (d, J=0.9 Hz, 1H), 8.35 (d, J=1.1 Hz, 1H), 7.92 (d, J=1.1 Hz, 1H), 7.88 (d , J=2.4 Hz, 1H), 7.83 - 7.78 (m, 1H), 7.74 - 7.69 (m, 1H), 6.39 (d, J=0.9 Hz, 1H).

intermediate 9

Preparation of 6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol

9A. Preparation of 4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

2-Bromo-4-chloroaniline (3 g, 14.53 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolane) in a 20 mL microwave vial. -2-yl)-1,3,2-dioxaborolane (5.53 g, 21.80 mmol), KOAc (3.66 g, 37.3 mmol), Pd(dppf)Cl ₂ -CH ₂ Cl ₂ adduct (0.32 g, 0.44 mmol) and DMSO (9 mL) were added. The resulting suspension was purged with N ₂ , capped and heated at 80° C. for 22 hours. The reaction was cooled to room temperature. Water was added to dissolve the salt, and then the reaction was filtered. The remaining solid was suspended in DCM and the insoluble solid was filtered. The filtrate was concentrated and then purified by normal phase chromatography to obtain 4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.15 g, 86% yield) as white. Obtained as a solid. MS(ESI) m/z:172.3 (MC ₆ H ₁₀ +H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 7.54 (d, J=2.6 Hz, 1H), 7.13 (dd, J=8.8, 2.6 Hz, 1H), 6.52 (d, J=8.6 Hz, 1H), 4.72 ( br. s., 2H), 1.34 (s, 12H).

9B. Preparation of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline

4-Chloro-6-methoxypyrimidine (3.13 g, 21.62 mmol), 4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7.31 g, 21.62 mmol) ), Na ₂ CO ₃ (2.29 g, 21.62 mmol), DME (86 ml), EtOH (10.81 ml) and water (10.81 ml) were equipped with a condenser. The mixture was purged with Ar for a few minutes, then Pd(dppf)Cl ₂ -CH ₂ Cl ₂ adduct (1.77 g, 2.16 mmol) was added. The reaction was heated at 90°C for 5 hours. The reaction was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was washed with brine, concentrated and purified by normal phase chromatography to give 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (2.86 g, 56.1% yield) as a yellow solid. did. MS(ESI) m/z: 236.0 (M+H) ⁺ .

^1H NMR (500MHz, CDCl ₃ ) δ 8.78 (d, J=1.1 Hz, 1H), 7.49 (d, J=2.5 Hz, 1H), 7.15 (dd, J=8.8, 2.5 Hz, 1H), 6.99 ( d, J=1.1 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 5.89 (br. s., 2H), 4.03 (s, 3H).

9C. Preparation of 4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine

To a solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (1.5 g, 6.36 mmol) in ACN (90 ml) at 0° C. was added 3-methylbutyl nitrite (1.28 ml, 9.55 mmol). ) was added, and then TMSN ₃ (1.26 ml, 9.55 mmol) was added dropwise. Gas evolution was observed. After 10 minutes, the ice bath was removed and the reaction was allowed to warm to room temperature. After 1 hour, ethynyltrimethylsilane (2.72 ml, 19.09 mmol) and Cu ₂ O (0.09 g, 0.64 mmol) were added and the reaction was stirred for an additional 1 hour. The reaction was partitioned between EtOAc and saturated NH ₄ Cl and the layers were separated. The organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated. Purified by normal phase chromatography, 4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine (2.13 g, 5.92 mmol, 93% yield) was obtained as a yellow solid. MS(ESI) m/z: 360.3 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.71 (d, J=1.1 Hz, 1H), 7.82 (d, J=2.2 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.54 - 7.48 (m, 2H) ), 6.20 (d, J=1.1 Hz, 1H), 3.92 (s, 3H), 0.32 - 0.28 (m, 9H).

9D. Preparation of 4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine

4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine (1.56 g) in ACN (28.9 ml) , 4.33 mmol), NCS (2.03 g, 15.17 mmol) and silica gel (6.51 g, 108 mmol) were added. The reaction was stirred at 80°C for 1 hour. The reaction was then filtered to remove silica gel, and the collected silica gel was washed with EtOAc. The filtrate was washed with water (2x), brine and concentrated. Purified by normal phase chromatography, 4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine (0.90 g, 64.5 % yield) was obtained as a yellow foam. MS(ESI) m/z: 322.3 (M+H) ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 8.70 (d, J=1.1 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.66 - 7.55 (m, 2H), 7.50 (d, J=8.6) Hz, 1H), 6.52 (d, J=0.9 Hz, 1H), 3.98 (s, 3H).

9E. Preparation of 6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol

4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine (900 mg, 2.79 mmol) in AcOH (6 ml) ) was added to a solution of 48% aqueous HBr (3 ml, 26.5 mmol). The mixture was stirred at 85°C for 1 hour. The reaction was concentrated to dryness and then partitioned between EtOAc and saturated NaHCO ₃ . The mixture was separated and the aqueous layer was extracted with EtOAc (2x). The organic layers were combined, concentrated, and the residue was purified by normal phase chromatography to give a white solid. The solid was suspended in Et ₂ O, filtered and washed with Et ₂ O to give 6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyri. Midin-4-ol (610 mg, 70.9% yield) was obtained as a white solid. MS(ESI) m/z: 308.3 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.74 - 7.67 (m, 2H), 7.62 (dd, J=8.5, 2.3 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H ), 6.44 (d, J=0.9 Hz, 1H).

intermediate 10

Preparation of 6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol

10A. Preparation of N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide

TFAA (12.23 mL) in a suspension of 4-chloro-3-fluoroaniline (10.67 g, 73.3 mmol) and Na ₂ CO ₃ (24.5 g, 125 mmol) in Et ₂ O (300 mL) at -10°C under N ₂ , 88 mmol) was added dropwise. The mixture was allowed to warm to room temperature and then stirred for 18 hours. The reaction mixture was diluted with hexane (300 mL) and filtered. The filtrate was washed with ice water, 10% aqueous NaHCO ₃ , and brine, dried over Na ₂ SO ₄ and concentrated. A light yellow solid was obtained as N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (17 g, 96% yield). MS(ESI) m/z: 242.1 (M+H) ⁺ .

10B. Preparation of (6-amino-3-chloro-2-fluorophenyl)boronic acid

To a cooled (-78° C.) clear, colorless solution of N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (5 g, 20.70 mmol) in THF (69.0 ml). 2.5 M BuLi (16.56 ml, 41.4 mmol) in hexane was added dropwise over 15 minutes while maintaining the internal temperature below -60°C. The resulting clear yellow solution was stirred at -78°C for 10 minutes and then the reaction was allowed to warm to -50°C over 1 hour. The resulting transparent brown solution was cooled to -78°C, and then B(O-iPr) ₃ (10.51 ml, 45.5 mmol) was added dropwise. The reaction was stirred at -78°C for 10 minutes, then the ice bath was removed and the reaction was allowed to warm to room temperature. The resulting orange suspension was stirred at room temperature for 2 hours, then cooled in an ice bath and quenched with 1 N HCl (40 ml). The reaction mixture was warmed to 40° C. for 1 hour and then cooled to room temperature. The reaction was diluted with EtOAc and the layers were separated. The organic layer was washed with brine and concentrated. Purification by normal phase chromatography gave (6-amino-3-chloro-2-fluorophenyl)boronic acid (3 g, 76.6% yield). MS(ESI) m/z: 190.1 (M+H) ⁺ .

10C. Preparation of 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline

The reaction was carried out in a 350 ml pressure bottle. 4-Chloro-6-methoxypyrimidine (1.784 g, 12.34 mmol), (6-amino-3-chloro-2-fluorophenyl)boronic acid (3.3 g) in toluene (25 ml) and EtOH (25 ml) , 12.34 mmol) was purged with N ₂ for several minutes. DIEA (4.31 ml, 24.68 mmol) was added followed by Pd(Ph ₃ P) ₄ (1.426 g, 1.234 mmol). The flask was capped and the reaction was heated at 120° C. for 2 hours, then cooled to room temperature and concentrated. Purification by normal phase chromatography gave 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (2 g, 45.2% yield) as a yellow solid. MS(ESI) m/z: 254.0 (M+H) ⁺ .

10D. Preparation of 4-(3-chloro-2-fluoro-6-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine

To a cooled (0° C.), clear yellow solution of 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (2.1 g, 8.28 mmol) in ACN (118 ml) Amynitrite (1.67 ml, 12.42 mmol) was added followed by TMSN ₃ (1.63 ml, 12.42 mmol) dropwise. After 10 minutes, the cooling bath was removed and the reaction was allowed to warm to room temperature. After 2 hours, ethynyltrimethylsilane (3.54 ml, 24.84 mmol) and Cu ₂ O (0.118 g, 0.83 mmol) were added, and the reaction was stirred at room temperature for 1.5 hours. The reaction was then diluted with EtOAc, washed with saturated NH ₄ Cl, brine, dried over MgSO ₄ , filtered and concentrated to give a brown oil. Purified by normal phase chromatography, 4-(3-chloro-2-fluoro-6-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy Cipyrimidine (2.71 g, 87% yield) was obtained as a brown solid. MS(ESI) m/z: 378.1 (M+H) ⁺ .

10E. Preparation of 4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine

4-(3-chloro-2-fluoro-6-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6 in a RBF equipped with stir bar and condenser. -Methoxypyrimidine (2.71 g, 7.17 mmol), NCS (3.35 g, 25.1 mmol), and silica gel (10.77 g, 179 mmol) were added followed by ACN (47.8 ml). The reaction was heated at 80°C for 1 hour and then cooled to room temperature. The reaction was filtered and the filtrate was concentrated. The residue was redissolved in EtOAc, washed with saturated NaHCO ₃ , water, brine and concentrated. Purified by normal phase chromatography, 4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine (1.05 g, 43.0% yield) was obtained as a yellow solid. MS(ESI) m/z: 340.0 (M+H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.68 (d, J=0.7 Hz, 1H), 7.71 - 7.62 (m, 2H), 7.37 (dd, J=8.6, 1.8 Hz, 1H), 6.84 (s, 1H) ), 4.02 (s, 3H).

10F. Preparation of 6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl) pyrimidin-4-ol

4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2- in HOAc (15.43 ml) and 48% aqueous HBr (17.46 ml, 154 mmol) A clear yellow solution of fluorophenyl)-6-methoxypyrimidine (1.05 g, 3.09 mmol) was warmed to 65° C. for 3 hours, then cooled to room temperature and concentrated. The yellow gum was suspended in EtOAc, washed with saturated NaHCO ₃ (2x), brine, dried over Na ₂ SO ₄ , filtered and concentrated. To the residue was added Et ₂ O (10 ml) and the resulting suspension was sonicated and then filtered. The solid was rinsed with Et ₂ O (2 ml) and air-dried under suction to give 6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2- Fluorophenyl)pyrimidin-4-ol (0.79 g, 78% yield) was obtained as a white solid. MS(ESI) m/z: 326.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.35 (s, 1H), 8.08 (d, J=0.7 Hz, 1H), 7.85 (dd, J=8.7, 7.6 Hz, 1H), 7.54 (dd, J= 8.6, 1.5 Hz, 1H), 6.57 (s, 1H).

Intermediate 11

Preparation of 6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

11A. Preparation of 4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine

Iso-cooled to a cooled (0° C.), clear yellow solution of 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (0.2 g, 0.79 mmol) in ACN (11.26 ml). Amylnitrite (0.16 mL, 1.18 mmol) was added followed by TMSN ₃ (0.16 mL, 1.18 mmol) dropwise. After 10 minutes, the cooling bath was removed and the reaction was allowed to warm to room temperature. After 2 hours, Cu ₂ O (0.011 g, 0.079 mmol) was added. 3,3,3-Trifluoroprop-1-yne (0.5 mL, 0.79 mmol) gas was bubbled through the reaction for 5 minutes, then the reaction was capped and stirred at room temperature. After 1 hour, the reaction was diluted with EtOAc, washed with saturated NH ₄ Cl, brine, dried over MgSO ₄ , filtered and concentrated to give a brown oil. Purified by normal phase chromatography, 4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6 -Methoxypyrimidine (0.24 g, 81% yield) was obtained as a yellow solid. MS(ESI) m/z: 374.3 (M+H) ⁺ .

11B. Preparation of 6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3- in HOAc (1.34 ml) and 48% aqueous HBr (1.51 ml, 13.38 mmol) A clear yellow solution of triazol-1-yl)phenyl)-6-methoxypyrimidine (0.1 g, 0.268 mmol) was warmed to 65° C. for 3 hours, then cooled to room temperature and concentrated. The yellow gum was suspended in EtOAc, washed with saturated NaHCO ₃ (2x), brine, dried over Na ₂ SO ₄ , filtered and concentrated. To the residue was added Et ₂ O (3 ml) and the resulting suspension was sonicated and then filtered. The solid was rinsed with Et ₂ O (2 ml) and air-dried under suction to give 6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3- Triazol-1-yl)phenyl)pyrimidin-4-ol (0.07 g, 72.7% yield) was obtained as a white solid. MS(ESI) m/z: 360.0 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.84 (s, 1H), 8.03 (br. s., 1H), 7.91 - 7.84 (m, 1H), 7.58 (dd, J=8.8, 1.5 Hz, 1H) , 6.61 (br. s., 1H).

intermediate 12

Preparation of 1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbonitrile

12A. Preparation of 1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide

To a cooled (0° C.), clear yellow solution of 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (1 g, 3.94 mmol) in ACN (56.3 ml) Amynitrite (0.79 ml, 5.91 mmol) was added followed by TMSN ₃ (0.79 ml, 5.91 mmol) dropwise. After 10 minutes, the cooling bath was removed and the reaction was allowed to warm to room temperature and stirred at room temperature for 1 hour. Next, propiolamide (0.817 g, 11.83 mmol) and Cu ₂ O (0.056 g, 0.394 mmol) were added. After 1 hour, the yellow cloudy reaction was diluted with EtOAc, washed with saturated NH ₄ Cl, brine, dried over MgSO ₄ , filtered and concentrated to give a yellow solid. DCM (10 ml) was added and the resulting mixture was sonicated. The suspension was filtered and the solid was air-dried. The yellow solid was reacted with 1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide (1.003 g, 73.0% yield). MS(ESI) m/z: 349.0 (M+H) ⁺ .

12B. Preparation of 1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbonitrile

1-(4-Chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic in EtOAc (13 ml) To a suspension of amide (1.003 g, 2.88 mmol) was added TEA (1.20 ml, 8.63 mmol) followed by dropwise addition of T3P® (50% in EtOAc) (5.14 ml, 8.63 mmol). The reaction was microwaved at 120°C for 30 minutes and then cooled to room temperature. The reaction was diluted with EtOAc, washed with saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a brown solid. Purified by normal phase chromatography, 1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbon Trill (0.815 g, 86% yield) was obtained as a yellow solid. MS(ESI) m/z: 331.1 (M+H) ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 8.62 (d, J=1.1 Hz, 1H), 8.21 (s, 1H), 7.72 (dd, J=8.6, 7.5 Hz, 1H), 7.39 (dd, J=8.6) , 1.8 Hz, 1H), 6.89 (dd, J=1.9, 1.2 Hz, 1H), 4.03 (s, 3H).

12C. Preparation of 1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbonitrile

1-(4-Chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbonitrile in ACN (16.33 ml) To a suspension of (0.81 g, 2.449 mmol) was added TMSI (2.00 ml, 14.70 mmol) at room temperature, and then the clear solution was heated to 50°C. After 18 hours, the reaction was cooled to room temperature. The reaction was poured into 10% Na ₂ S ₂ O ₃ solution and extracted with EtOAc (3x). The combined organic layers were washed with saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a residue. The residue was suspended in DCM (20 ml), filtered, the solid was rinsed with DCM and air-dried to give 1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl). )Phenyl)-1H-1,2,3-triazole-4-carbonitrile (0.73 g, 94% yield) was obtained as a white solid. MS(ESI) m/z: 317.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.97 (s, 1H), 8.04 (s, 1H), 7.91 - 7.85 (m, 1H), 7.58 (dd, J=8.8, 1.5 Hz, 1H), 6.62 ( s, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -114.93 (s, 1F).

Intermediate 13

Preparation of 6-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol hydrobromide

13A. Preparation of 4-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine

To a cooled (0° C.), clear yellow solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (0.100 g, 0.42 mmol) in ACN (6.06 ml) was added isoamylnitrite (0.086 ml). ml, 0.64 mmol) was added, followed by the dropwise addition of TMSN ₃ (0.084 ml, 0.64 mmol). After 10 minutes, the cooling bath was removed, the reaction was allowed to warm to room temperature, and the reaction was stirred at room temperature for 1 hour. Next, ethynylcyclopropane (0.120 g, 1.27 mmol) and Cu ₂ O (6.07 mg, 0.042 mmol) were added. The flask was equipped with a reflux condenser and the reaction was heated to 50° C. for 1 hour and then the reaction was cooled to room temperature. The reaction was diluted with DCM, washed with saturated NH ₄ Cl, brine, dried over MgSO ₄ , filtered and concentrated to give a brown oil. Purification by normal phase chromatography followed by reverse phase chromatography gave 4-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimi. Dean (0.024 g, 17.3% yield) was obtained as a yellow oil. MS(ESI) m/z: 328.1 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.75 (d, J=0.9 Hz, 1H), 7.79 (d, J=2.2 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.51 - 7.47 (m, 1H) ), 7.29 (s, 1H), 6.35 (d, J=0.9 Hz, 1H), 3.96 (s, 3H), 1.96 (tt, J=8.4, 5.0 Hz, 1H), 1.02 - 0.95 (m, 2H) , 0.88 - 0.81 (m, 2H).

13B. Preparation of 6-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol hydrobromide.

4-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl) in HOAc (0.73 ml) and 48% aqueous HBr (0.41 ml, 3.66 mmol) A clear yellow solution of -6-methoxypyrimidine (0.024 g, 0.073 mmol) was warmed to 65° C. for 3 hours, then cooled to room temperature and concentrated. The yellow gum was suspended in EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Et ₂ O (3 ml) was added to the residue, sonicated and filtered. The solid was rinsed with Et ₂ O (2 ml) and air-dried under suction to obtain 6-(5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl) Pyrimidin-4-ol hydrobromide (0.03 g, 100% yield) was obtained as a yellow solid. MS(ESI) m/z: 314.0 (M+H) ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.67 (d, J=0.7 Hz, 1H), 8.22 (s, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.82 (dd, J=8.6, 2.2 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 6.48 (d, J=0.9 Hz, 1H), 2.11 - 2.01 (m, 1H), 1.11 - 1.04 (m, 2H), 0.91 - 0.84 (m, 2H).

Intermediate 14

Preparation of 6-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol

14A. Preparation of 4-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine

To a cooled (0° C.), clear yellow solution of 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (0.100 g, 0.39 mmol) in ACN (5.6 ml) Amynitrite (0.079 ml, 0.59 mmol) was added followed by TMSN ₃ (0.078 ml, 0.59 mmol) dropwise. After 10 minutes, the cooling bath was removed and the reaction was allowed to warm to room temperature. After 1 hour, ethynylcyclopropane (0.112 g, 1.18 mmol) and Cu ₂ O (5.64 mg, 0.039 mmol) were added. The flask was equipped with a reflux condenser and the reaction was heated to 50° C. for 1 hour and then the reaction was cooled to room temperature. The reaction was diluted with DCM, washed with saturated NH ₄ Cl, brine, dried over MgSO ₄ , filtered and concentrated to give a brown oil. Purified by normal phase chromatography, 4-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimi Dean (0.05 g, 36.7% yield) was obtained as a yellow oil. MS(ESI) m/z: 346.0 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.69 (d, J=0.9 Hz, 1H), 7.63 (dd, J=8.6, 7.5 Hz, 1H), 7.35 (dd, J=8.6, 1.5 Hz, 1H), 7.30 (s, 1H), 6.76 (t, J=1.2 Hz, 1H), 4.00 (s, 3H), 1.90 (tt, J=8.4, 5.0 Hz, 1H), 0.98 - 0.91 (m, 2H), 0.82 - 0.76 (m, 2H).

14B. Preparation of 6-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl) pyrimidin-4-ol

4-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2 in HOAc (1.45 ml) and 48% aqueous HBr (0.82 ml, 7.23 mmol) A clear yellow solution of -fluorophenyl)-6-methoxypyrimidine (0.05 g, 0.145 mmol) was warmed to 65° C. for 3 hours, then the reaction was cooled to room temperature and concentrated. Purified by reverse phase chromatography, 6-(3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol (0.04 g, 83% yield) was obtained as a yellow solid. MS(ESI) m/z: 332.0 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.09 (d, J=0.9 Hz, 1H), 7.91 (s, 1H), 7.82 (dd, J=8.6, 7.7 Hz, 1H), 7.49 (dd, J= 8.8, 1.5 Hz, 1H), 6.50 - 6.47 (m, 1H), 1.97 (tt, J=8.5, 5.1 Hz, 1H), 1.01 - 0.95 (m, 2H), 0.81 - 0.75 (m, 2H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -115.39 (s).

intermediate 15

Preparation of 6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol

15A. Preparation of 4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine

3-methylbutyl in a solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (1.0 g, 4.24 mmol) prepared as described in Intermediate 9B in ACN (60.6 ml) at 0°C. Nitrite (0.86 ml, 6.36 mmol) was added followed by TMSN ₃ (0.84 ml, 6.36 mmol) dropwise. Gas evolution was observed. After 10 minutes, the ice bath was removed and the reaction was allowed to warm to room temperature. After 2 hours, Cu ₂ O (61 mg, 0.42 mmol) was added, followed by slow bubbling of 3,3,3-trifluoroprop-1-yne gas over a period of 5 minutes. After an additional 10 minutes, the reaction was partitioned between DCM and saturated NH ₄ Cl and the layers were separated. The organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated. Purified by normal phase chromatography, 4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine (1.46 g, 97% yield) was obtained as a yellow solid. MS(ESI) m/z: 356.1 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.62 (d, J=1.1 Hz, 1H), 8.00 (d, J=0.7 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.66 - 7.60 ( m, 1H), 7.52 (d, J=8.6 Hz, 1H), 6.60 (d, J=1.1 Hz, 1H), 3.98 (s, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -61.10 (s).

15B. Preparation of 6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl} pyrimidin-4-ol

4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine (1.46) in AcOH (10 ml) g, 4.10 mmol) was added 48% aqueous HBr (5 ml, 44.2 mmol). The mixture was stirred at 85°C for 1 hour. The reaction was concentrated to dryness and then partitioned between EtOAc and saturated NaHCO ₃ . The layers were separated and the aqueous layer was extracted with EtOAc (2x). The organic layers were combined, washed with saturated NaHCO ₃ , brine, dried over MgSO ₄ , filtered and the solvent was reduced under vacuum until some solids began to form. The resulting suspension was triturated with Et ₂ O. The solid was filtered, washed with Et ₂ O and 6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidine- 4-ol (1 g, 71.3% yield) was obtained as a light yellow solid. MS(ESI) m/z: 342.0 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.83 (d, J=0.7 Hz, 1H), 7.99 (d, J=0.9 Hz, 1H), 7.87 (d, J=2.2 Hz, 1H), 7.79 - 7.72 (m, 1H), 7.70 - 7.62 (m, 1H), 6.45 (d, J=0.9 Hz, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -62.61 (s).

intermediate 16

Preparation of 6-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol

16A. Preparation of {1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazol-4-yl}methanol

{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazol-4-yl}methanol (0.44 g, 52.5% yield) For the preparation of 4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine as described in Intermediate 9C. was prepared in a similar manner to the procedure described for, replacing ethynyltrimethylsilane with propargyl alcohol (0.38 ml, 6.36 mmol). MS(ESI) m/z: 318.3 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.66 (d, J=1.1 Hz, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.63 (s, 1H), 7.61 - 7.55 (m, 1H), 7.51 - 7.46 (m, 1H), 6.42 (d, J=1.1 Hz, 1H), 4.77 (d, J=5.9 Hz, 2H), 3.93 (s, 3H).

16B. Preparation of 1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbaldehyde

{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazol-4-yl}methanol (95 mg) in DMSO (1 mL) , 0.3 mmol) was added to the solution of IBX (92 mg, 0.33 mmol), and the reaction was stirred at room temperature for 14 hours. Water and saturated NaHCO ₃ were added and the mixture was extracted with EtOAc (2x). The organic layers were combined, concentrated and purified by normal phase chromatography to give 1-[4-chloro-2-(6-methoxy pyrimidin-4-yl)phenyl]-1H-1,2,3-triazole- 4-Carbaldehyde (82 mg, 87% yield) was obtained as a white solid. MS(ESI) m/z: 316.3 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 10.16 (s, 1H), 8.62 (d, J=1.1 Hz, 1H), 8.21 (s, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.64 ( dd, J=8.5, 2.3 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 6.59 (d, J=1.1 Hz, 1H), 3.97 (s, 3H).

16C. Preparation of 4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine

1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbaldehyde (427 mg, DAST (0.54 ml, 4.1 mmol) was added to the solution (1.35 mmol) and the reaction was stirred at room temperature overnight. The reaction was quenched with water and extracted with DCM. The organic layer was concentrated and purified by normal phase chromatography to give 4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}- 6-Methoxypyrimidine (441 mg, 97% yield) was obtained as a yellow solid. MS(ESI) m/z: 338.3 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.65 (d, J=0.9 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.62 (dd, J=8.5, 2.3 Hz, 1H), 7.55 - 7.47 (m, 1H), 6.89 (t, J=54.6 Hz, 1H), 6.52 (d, J=1.1 Hz, 1H), 4.03 - 3.87 (m, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -112.40 (s).

16D. Preparation of 6-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl} pyrimidin-4-ol

6-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (370 mg, 88% yield) as described for the preparation of 6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol, as described in Intermediate 9E. In a similar manner to the procedure, 4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine was reacted with 4-{5- Prepared by replacing chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine (441 mg, 1.31 mmol) . MS(ESI) m/z: 324.3 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.04 (s, 1H), 7.86 (s, 1H), 7.71 (d, J=2.2 Hz, 1H), 7.67 - 7.61 (m, 1H), 7.51 (d, J =8.6 Hz, 1H), 6.92 (t, J=54.6 Hz, 1H), 6.43 (d, J=0.7 Hz, 1H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -112.69 (s).

Intermediate 17

Preparation of 6-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol

17A. Preparation of 4-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-methoxypyrimidine

To 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (300 mg, 1.183 mmol) dissolved in AcOH (3 mL) was added trimethoxymethane (377 mg, 3.55 mmol) was added and stirred. After 30 minutes, NaN ₃ (231 mg, 3.55 mmol) was added and stirred at room temperature for 16 hours. Water was added to the reaction mixture and a precipitate formed. The mixture was filtered to collect the solid residue, the filtrate was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated to give the crude solid, which was then quenched with the original solid collected. Combined with the residue. The crude material was purified by normal phase chromatography to obtain 4-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-6-methoxypyrimidine (367 mg, 100% yield) ) was obtained. MS(ESI) m/z: 307.08 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.78 (s, 1H), 8.59 (d, J=1.1 Hz, 1H), 7.71 (dd, J=8.7, 7.4 Hz, 1H), 7.38 (dd, J=8.6) , 1.8 Hz, 1H), 6.86 (dd, J=1.9, 1.2 Hz, 1H), 3.98 (s, 3H).

17B. Preparation of 6-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol

4-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-6-methoxypyrimidine (50 mg, 0.163 mmol), NaI, dissolved in ACN (1.6 ml) TMSCl (0.2 ml, 1.630 mmol) was added to the solution (244 mg, 1.630 mmol). The resulting reaction mixture was stirred at room temperature for 23 hours. Celite® was added to the reaction mixture, the slurry was filtered, and the collected organics were concentrated to give a crude solid. Purified by normal phase chromatography, followed by trituration with Et ₂ O, 6-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl ]Pyrimidin-4-ol (46 mg, 96% yield) was obtained as a white solid. MS(ESI) m/z: 293.08 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.75 (s, 1H), 8.40 (s, 1H), 8.28 (dd, J=8.7, 7.6 Hz, 1H), 7.97 (dd, J=8.7, 1.7 Hz, 1H), 7.02 (s, 1H).

intermediate 18

Preparation of 1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile

18A. Preparation of 1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide

1-[4-Chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide (300 mg, 80% yield) was used as an intermediate. For the preparation of 4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine as described in 9C It was prepared in a similar manner to the procedure described, replacing ethynyltrimethylsilane with prop-2-ynamide (176 mg, 2.55 mmol). MS(ESI) m/z: 331.4 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.66 (d, J=0.7 Hz, 1H), 8.16 (s, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.62 (dd, J=8.5, 2.3 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.05 (br. s., 1H), 6.53 (d, J=0.9 Hz, 1H), 5.66 (br. s., 1H), 3.97 (s, 3H).

18B. Preparation of 1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile

1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide (91 mg, To a suspension of 0.28 mmol) and TEA (115 μl, 0.83 mmol) was added dropwise T3P® (50% in EtOAc) (0.49 ml, 0.83 mmol). The reaction was microwaved at 120°C for 1 hour. Additional TEA (115 μl, 0.83 mmol) and T3P® (50% in EtOAc) (0.49 ml, 0.83 mmol) were added and the reaction was microwaved at 120° C. for an additional 30 min. The reaction was diluted with EtOAc, washed with water, saturated NaHCO ₃ , brine, dried over MgSO ₄ , filtered and concentrated. Purified by normal phase chromatography, 1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile (91 mg, 100% yield) was obtained as a white solid. MS(ESI) m/z: 313.3 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.62 (d, J=0.9 Hz, 1H), 8.17 (s, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.65 (dd, J=8.5, 2.3 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 6.65 (d, J=1.1 Hz, 1H), 4.00 (s, 3H).

18C. Preparation of 1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile

1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile (91 mg, 0.29) in ACN (3 mL) mmol), TMSI (0.2 mL, 1.47 mmol) was added at room temperature, and the solution was heated at 50°C for 15 hours. The reaction was poured into 10% Na ₂ S ₂ O ₃ and saturated NaHCO ₃ and then extracted with EtOAc (3x). The combined organic layers were washed with brine. Upon standing, solids precipitated out from the organic layer. The solid was filtered, rinsed with EtOAc, and air-dried to give 1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4- Carbonitrile (60 mg, 69.0% yield) was obtained as a white solid. MS(ESI) m/z: 299.3 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.22 (s, 1H), 7.91 (s, 1H), 7.72 (d, J=2.2 Hz, 1H), 7.66 (dd, J=8.5, 2.3 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 6.55 (s, 1H).

Intermediate 19

(9R,13S)-13-amino-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] Preparation of octadeca-1(18),2(6),4,14,16-pentaen-8-one

19A. Preparation of 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

To a solution of 4-nitro-1H-pyrazole (5.0 g, 44.2 mmol) in THF (100 mL) at 0° C. was added N-cyclohexyl-N-methylcyclohexanamine (0.948 mL, 4.43 mmol), followed by SEM-Cl (12.55 mL, 70.7 mmol) was added dropwise. The reaction mixture was then allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was concentrated and purified by normal phase chromatography to give 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole as a clear oil (2.4 g, 21% yield. ).

^1H NMR (500MHz, CDCl ₃ ) δ 8.31 (s, 1H), 8.10 (s, 1H), 5.46 (s, 2H), 3.67 - 3.55 (m, 2H), 0.99 - 0.90 (m, 2H), 0.05 - 0.03 (m, 9H).

19B. (S)-Benzyl (1-(4-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3 -N-1-yl) Preparation of carbamate

(S)-Benzyl (1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (1.9 g, prepared as described in Intermediate 23) in an N ₂ flushed pressure vial. 6.00 mmol), 4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.6 g, 6.60 mmol), di(adamant-) prepared as described in Intermediate 41A 1-yl)(butyl)phosphine (0.323 g, 0.90 mmol), PvOH (0.209 mL, 1.80 mmol) and K ₂ CO ₃ (2.48 g, 17.9 mmol) were added. N,N-dimethylacetamide (45 mL) was then added to this mixture and the vial was purged with N ₂ for 5 minutes. Then, Pd(OAc) ₂ (0.135 g, 0.600 mmol) was added to this mixture. The reaction mixture was purged again with N ₂ . The vial was sealed and heated in the microwave at 120°C for 1 hour. The reaction mixture was cooled to room temperature and partitioned between 10% aqueous LiCl (15 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic layers were washed with brine (15 mL) and dried over MgSO ₄ . The crude product was then purified using normal phase chromatography to (S)-benzyl (1-(4-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (1.92 g, 58% yield) was obtained as a brown oil. MS(ESI) m/z: 524.2 (M+H) ⁺ .

19C. (S)-Benzyl(1-(4-(4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3 -N-1-yl) Preparation of carbamate

(S)-Benzyl (1-(4-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl prepared as described in Intermediate 41B in MeOH (20 mL) and AcOH (2 mL) )-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (1.92 g, 3.68 mmol) was heated at 40°C. Then, Zn (0.481 g, 7.35 mmol, 3 parts (50:25:25%)) was slowly added to the transparent solution and stirred at the same temperature for 5 minutes. The reaction mixture was monitored by LCMS and upon completion, 2.0 g of K ₂ CO ₃ (1 g for 1 mL AcOH) and 2 mL water were added to the cooled reaction mixture. The reaction mixture was stirred for 5 minutes and then filtered over a pad of Celite® and concentrated to give the crude product. The crude product was then partitioned between EtOAc (30 mL) and saturated NaHCO ₃ (15 mL) solutions. The organic layer was separated, dried over MgSO ₄ , filtered and concentrated. The crude product was then purified using normal phase chromatography to (S)-benzyl (1-(4-(4-amino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (1.15 g, 63% yield) was obtained as a light yellow oil. MS(ESI) m/z: 494.4 (M+H) ⁺ .

19D. Benzyl ((S)-1-(4-(4-((R)-2-methylbut-3-enamido)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyra Preparation of sol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

Solution (S)-benzyl (1-(4-(4-amino-1-((2-(trimethylsilyl)ethoxy) prepared as described in Example 41C in a 3-neck 250 mL RBF, flushed with N ₂ Methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (1.15 g, 2.33 mmol), and EtOAc (15 mL) were added. The solution was cooled to -10°C and (R)-2-methylbut-3-enoic acid (350 mg, 3.49 mmol), pyridine (0.564 mL, 6.99 mmol) and T3P® (2.77 mL) as prepared in Intermediate 2. , 4.66 mmol) was added. The cooling bath was removed and the solution was allowed to warm to room temperature and then stirred over a period of 20 hours. Water (20 mL) and EtOAc (20 mL) were added and the mixture was stirred for 30 minutes. The organic phase was separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by normal phase chromatography eluting with gradient hexane/EtOAc gave benzyl ((S)-1-(4-(4-((R)-2-methylbut-3-enamido)-1-((2 -(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (1.12 g, 79% yield) was obtained. . MS(ESI) m/z: 576.4 [M+H] ⁺ .

19E. Benzyl N-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl) ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3 Preparation of .1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

Benzyl ((S)-1-(4-(4-((R)-2-methylbut-) prepared as described for Intermediate 41D in DCE (18 mL) in a 250 mL, 3-neck RBF, flushed with N ₂ 3-enamido)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carba A solution of mate (1.12 g, 1.945 mmol) was added. The solution was aerated with Ar for 15 minutes. Second generation Grubbs catalyst (662 mg, 0.778 mmol) was added in one portion. The reaction mixture was heated in the microwave at 120° C. for 30 minutes. After cooling to room temperature, the solvent was removed and the residue was purified by normal phase chromatography eluting with a gradient of DCM/MeOH to give benzyl N-[(9R,10E,13S)-9-methyl-8-oxo-3. -{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, 10,14,16-hexaen-13-yl]carbamate (477 mg, 42% yield) was obtained as a tan solid. MS(ESI) m/z: 548.3 [M+H] ⁺ .

19F. (9R,13S)-13-amino-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] Preparation of octadeca-1(18),2(6),4,14,16-pentaen-8-one

Pd/C (0.93 g, 0.871 mmol) was reacted with benzyl N-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2 prepared as described in Intermediate 41E in EtOH (20 mL). -(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14, A solution of 16-hexaen-13-yl]carbamate (477 mg, 0.871 mmol) was added to a 250 mL Parr hydrogenation flask. The flask was purged with N ₂ , pressurized with 55 psi of H ₂ and allowed to stir for 4 hours. The reaction was filtered through a pad of Celite® and concentrated to (9R,13S)-13-amino-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7, 15-Tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (245 mg, 64% yield) was obtained as a yellow-brown solid. It was obtained as. MS(ESI) m/z: 416.4 [M+H] ⁺ .

intermediate 20

Preparation of 6-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol

20A. Preparation of 4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-methoxypyrimidine

To a solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (0.507 g, 2.151 mmol) dissolved in AcOH (5.4 ml) was added trimethoxymethane (0.685 g, 6.45 mmol). And the resulting solution was stirred at room temperature for 30 minutes. Afterwards, NaN ₃ (0.420 g, 6.45 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. Water was added to form a precipitate. The precipitate was collected by filtration and the filtrate was extracted with EtOAc, which was then washed with brine, dried over MgSO ₄ , filtered and concentrated to give a crude solid. The combined solid residues were purified by normal phase chromatography to obtain 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-methoxypyrimidine (0.59 g, 95% yield) as an off-white color. Obtained as a solid. MS(ESI) m/z: 289.08 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.76 (s, 1H), 8.62 (d, J=0.9 Hz, 1H), 7.74 (d, J=2.2 Hz, 1H), 7.66 (dd, J=8.5, 2.3 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 6.65 (d, J=1.1 Hz, 1H), 3.99 (s, 3H).

20B. Preparation of 6-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol

4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-6-methoxypyrimidine (0.59 g, 2.044 mmol), NaI (3.06 g, 20.44 mmol) in ACN (20.44 ml) TMSCl (2.6 ml, 20.44 mmol) was added to the solution, and the reaction was stirred at room temperature for 16 hours. Celite® was added to the reaction mixture, and the slurry was filtered and concentrated to give a crude solid mixture. The solid was purified by normal phase chromatography and then recrystallized from EtOAc to give 6-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidine-4- All (370 mg, 66% yield) was obtained as a white solid. MS(ESI) m/z: 275.08 (M+H) ⁺ .

^1H NMR (400MHz, DMSO-d ₆ ) δ 12.62 (br. s., 1H), 9.72 (s, 1H), 7.97 (d, J=0.7 Hz, 1H), 7.92 (d, J=2.2 Hz, 1H), 7.87 - 7.83 (m, 1H), 7.82 - 7.78 (m, 1H), 6.48 (d, J=0.7 Hz, 1H).

intermediate 21

Preparation of 6-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol

21A. Preparation of (1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazol-4-yl)methanol

To a cooled (0° C.), clear yellow solution of 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (1.058 g, 4.17 mmol) in ACN (59.6 ml) Amynitrite (0.84 ml, 6.26 mmol) was added followed by TMSN ₃ (0.82 ml, 6.26 mmol) dropwise. After 10 minutes, the cooling bath was removed and the reaction was allowed to warm to room temperature. Propargyl alcohol (0.75 ml, 12.51 mmol) and Cu ₂ O (0.060 g, 0.42 mmol) were added. After 1 hour, the reaction was diluted with EtOAc, washed with saturated NH ₄ Cl, brine, dried over MgSO ₄ , filtered and concentrated to give a brown oil. The crude product was purified by normal phase chromatography to obtain (1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole. -4-yl)methanol (0.8 g, 57.1% yield) was obtained as a yellow foam. MS(ESI) m/z: 336.1 (M+H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.65 (d, J=1.1 Hz, 1H), 7.69 - 7.62 (m, 2H), 7.37 (dd, J=8.6, 1.5 Hz, 1H), 6.81 (t, J =1.2 Hz, 1H), 4.76 (d, J=5.9 Hz, 2H), 4.00 (s, 3H), 2.18 (t, J=6.1 Hz, 1H).

21B. Preparation of 1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbaldehyde

(1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazol-4-yl in DMSO (9.53 ml) ) IBX (0.734 g, 2.62 mmol) was added to a solution of methanol (0.8 g, 2.38 mmol), and the reaction was stirred at room temperature. After 18 hours, water and saturated NaHCO ₃ were added and the reaction mixture was extracted with EtOAc (2x). The organic layers were combined, dried over Na ₂ SO ₄ , filtered and concentrated. Purified by normal phase chromatography, 1-(4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-car Browndehyde (0.64 g, 80% yield) was obtained as a white solid. MS(ESI) m/z: 334.4 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 10.12 (s, 1H), 8.60 (d, J=1.1 Hz, 1H), 8.25 (s, 1H), 7.71 (dd, J=8.6, 7.5 Hz, 1H), 7.39 (dd, J=8.6, 1.8 Hz, 1H), 6.88 (dd, J=1.8, 1.1 Hz, 1H), 4.01 (s, 3H).

21C. Preparation of 4-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine

1-(4-Chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carb in DCM (24 ml) To a solution of aldehyde (0.3 g, 0.9 mmol) was added DAST (0.54 ml, 4.09 mmol). The reaction was stirred at room temperature for 22 hours. Water was added to the reaction, and the resulting mixture was extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purified by normal phase chromatography, 4-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6 -Methoxypyrimidine (0.256 g, 80% yield) was obtained as a white solid. MS(ESI) m/z: 356.1 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.62 (d, J=0.9 Hz, 1H), 7.94 (t, J=1.3 Hz, 1H), 7.69 (dd, J=8.6, 7.5 Hz, 1H), 7.39 ( dd, J=8.6, 1.8 Hz, 1H), 7.00 - 6.69 (m, 2H), 4.00 (s, 3H).

21D. Preparation of 6-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol

4-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazole-1- in HOAc (3.6 ml) and 48% aqueous HBr (4.07 ml, 36.0 mmol) A clear yellow solution of yl)-2-fluorophenyl)-6-methoxypyrimidine (0.256 g, 0.72 mmol) was warmed to 65° C. for 3 hours, then the reaction was cooled to room temperature and concentrated. The yellow gum was suspended in EtOAc, washed with saturated NaHCO ₃ (2x), brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was suspended in Et ₂ O (3 ml), sonicated and filtered. The solid was rinsed with Et ₂ O (2 ml) and air-dried under suction to give 6-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazole-1- Il)-2-fluorophenyl)pyrimidin-4-ol (0.23 g, 94% yield) was obtained as a yellow solid. MS(ESI) m/z: 342.0 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.56 (t, J=1.4 Hz, 1H), 8.05 (d, J=0.9 Hz, 1H), 7.86 (dd, J=8.6, 7.7 Hz, 1H), 7.57 (dd, J=8.7, 1.7 Hz, 1H), 6.98 (t, J=54.0 Hz, 1H), 6.58 (t, J=1.2 Hz, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -114.68 (s), -115.20 (s).

intermediate 22

Preparation of 6-(5-chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol

22A. Preparation of 7-bromo-5-chloro-1-methyl-1H-indazole

To a solution of 7-bromo-5-chloro-1H-indazole (5.0 g, 21.60 mmol) and K ₂ CO ₃ (14.93 g, 108 mmol) in DMSO (24.91 ml) at room temperature CH ₃ I (1.62 ml, 25.9 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with water and the resulting solid was filtered through a Buchner funnel, washed with water and dried under vacuum. The regioisomers were purified by normal phase chromatography eluting with a hexane/EtOAc gradient, with the first isomer eluting from the column being 7-bromo-5-chloro-1- as confirmed by ¹ H NMR and negative NOE. It was methyl-1H-indazole (2.83 g, 53.4%). MS(ESI) m/z: 245 (M+H) ⁺ and 247 (M+2+H) ⁺ .

^1H NMR (400MHz, DMSO-d ₆ ) δ 8.12 - 8.09 (m, 1H), 7.88 (d, J=1.8 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 4.32 (s, 3H) ).

22B. Preparation of 5-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

4,4,4',4',5,5 in a stirred solution of 7-bromo-5-chloro-1-methyl-1H-indazole (1.0 g, 4.07 mmol) in dioxane (20.37 ml) at room temperature. ,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.190 g, 4.68 mmol) and KOAc (1.839 g, 18.74 mmol) were added. The reaction was purged with Ar (3x). Pd(dppf)Cl ₂ DCM complex (0.266 g, 0.326 mmol) was added and the reaction was purged again with Ar and heated to 90°C. After stirring overnight, the reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAc (3x), washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude residue was purified by normal phase column chromatography eluting with gradient hexane/EtOAc to give 5-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxabor). Rolan-2-yl)-1H-indazole (0.47 g, 39.4% yield) oil was obtained, which slowly solidified upon standing. MS(ESI) m/z: 293.0 (M+H) ⁺ and 295.0 (M+2+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 7.94 (s, 1H), 7.80 (d, J=2.2 Hz, 1H), 7.71 (d, J=2.2 Hz, 1H), 4.23 (s, 3H), 1.40 (s, 12H).

22C. Preparation of 5-chloro-7-(6-methoxypyrimidin-4-yl)-1-methyl-1H-indazole

4-Chloro-6-methoxypyrimidine (0.201 g, 1.391 mmol), 5-chloro-1-methyl-7-(4,4,) in DME (5.56 ml)/EtOH (0.696 ml) in a large microwave vial. 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.407 g, 1.391 mmol), and 2 M aqueous Na ₂ CO ₃ (0.70 ml, 1.391 mmol) was added. The mixture was purged with Ar for a few minutes, PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.114 g, 0.139 mmol) was added and heated at 90°C. After 4 hours, the reaction mixture was cooled to room temperature, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give an orange-brown residue. The crude material was purified by normal phase column chromatography eluting with a hexane/EtOAc gradient to give 5-chloro-7-(6-methoxypyrimidin-4-yl)-1-methyl-1H-indazole (0.382, 100 %) was obtained as a solid. MS(ESI) m/z: 275.1 (M+H) ⁺ and 277.1 (M+2+H) ⁺ .

22D. Preparation of 6-(5-chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol

5-chloro-7-(6-methoxypyrimidin-4-yl)-1-methyl-1H-indazole (0.382 g, 1.391) in AcOH (3 ml) and 48% aqueous HBr (1.639 ml, 14.49 mmol) mmol) was warmed to 85°C. After 3 hours, the reaction mixture was concentrated. The residue was dissolved in EtOAc and washed with saturated NaHCO ₃ . The aqueous layer was extracted with additional EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting solid was suspended in Et ₂ O, filtered and dried under vacuum to give 6-(5-chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol (0.085 g, 23.5%). ) was obtained as a white solid. MS(ESI) m/z: 261.0 (M+H) ⁺ and 263.0 (M+2+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.78 (br. s., 1H), 8.32 (s, 1H), 8.13 (s, 1H), 7.97 (d, J=1.8 Hz, 1H), 7.46 - 7.36 (m, 1H), 6.66 (s, 1H), 3.87 (s, 3H).

intermediate 23

Preparation of tert-butyl N-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]carbamate

23A. Preparation of 4-chloro-2-[(E)-2-[(S)-2-methylpropane-2-sulfinyl]ethenyl]pyridine

To a solution of S-(-)-t-butyl-sulfinamide (0.856 g, 7.06 mmol) in DCM (14.13 mL) was added sequentially CuSO ₄ (2.481 g, 15.54 mmol) and 4-chloropicolinaldehyde (1.0 g, 7.06 mmol) was added. The white suspension was stirred at room temperature. After 3 hours, the brown suspension was filtered through Celite®, eluting with DCM, to give a clear brown filtrate. Concentration gave the crude product as a brown oil weighing 1.85 g. Purification by normal phase chromatography gave tert-butyl N-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]carbamate (1.31 g) as a clear yellow oil. It was obtained as. MS(ESI) m/z: 245.0 (M+H) ⁺ .

23B. Preparation of (R)-N-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide

To a cooled (0-5° C.) mixture of InCl ₃ (13.56 g, 61.3 mmol) in THF (170 mL) was added dropwise 1 M allylmagnesium bromide (62 mL, 61.3 mmol) in Et ₂ O over 30 min. The reaction was allowed to warm to room temperature. After 1 hour, 4-chloro-2-[(E)-2-[(S)-2-methylpropane-2-sulfinyl]ethenyl]pyridine (10 g, 40.9 mmol) in EtOH (170 mL) The solution was added to the reaction mixture. After 2-3 hours, the reaction was concentrated under vacuum at 50-55°C. The crude material was partitioned between EtOAc (200ml) and water (50ml) and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 50 ml). The organic layers were combined, washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give (R)-N-[(1S)-1-(4-chloropyridin-2-yl) But-3-en-1-yl]-2-methylpropane-2-sulfinamide (13.5 g, 106%) was obtained as a yellow oil. MS(ESI) m/z: 287.2 (M+H) ⁺ .

23C. Preparation of (1S)-1-(4-chloropyridin-2-yl)but-3-en-1-amine

(R)-N-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide (75 g, 261 mmol) was dissolved in MeOH (1500 mL). 6 N HCl (750 ml, 4.5 mol) was added. The reaction was stirred at room temperature for 2-3 hours and then concentrated. The residue was diluted with water (2 L) and washed with EtOAc (500 ml). The aqueous layer was basified with saturated aqueous Na ₂ CO ₃ and then extracted with EtOAc (3 x 1 L). The combined organic layers were washed with water (1 L) and brine (1 L), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo at 50-55° C. to give (1S)-1-(4-chloropyridine. -2-day) But-3-en-1-amine (43 g, 90%) was obtained. MS(ESI) m/z: 183.2 (M+H) ⁺ .

23D. Preparation of tert-butyl N-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]carbamate

(1S)-1-(4-Chloropyridin-2-yl)but-3-en-1-amine (42 g, 230 mmol) was dissolved in DCM (420 mL) and Et ₃ N (32.1 mL, 230 mmol). ) was added, and then BOC ₂ O (53.4 mL, 230 mmol) was added dropwise. The reaction was stirred at room temperature for 2-3 hours. The reaction was diluted with excess DCM (1 L) and washed with water (500 ml) and brine (500 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified using silica gel chromatography to obtain tert-butyl N-[(1S)-1-(4-chloropyridin-2-yl)but-3-en-1-yl]carbamate (61 g) , 86%) was obtained as a light yellow solid. MS(ESI) m/z: 283.2 (M+H) ⁺ .

^1H NMR (500 MHz, CDCl ₃ ) δ 8.44 (d, 1H), 7.26-7.16 (dd, 2H), 5.69-5.61 (m, 1H), 5.59 (bs, 1H), 5.07-5.03 (m, 2H) ), 4.76 (bs, 1H), 2.62-2.55 (m, 2H), 1.42 (s, 9H).

intermediate 24

Preparation of tert-butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate

24A. Preparation of (R)-N-[(1E)-(3-bromophenyl)methylidene]-2-methylpropane-2-sulfinamide

To 3-bromobenzaldehyde (7.8 g, 42.2 mmol), (R)-2-methylpropane-2-sulfinamide (5.11 g, 42.2 mmol) in DCM (211 ml), Cs ₂ CO ₃ (20.60 g, 63.2 mmol) was added, and the resulting reaction mixture was stirred for 5 days. The reaction mixture was then partitioned using brine (50 ml) and DCM (50 ml). The aqueous layer was extracted with DCM (2 x 50 ml). The combined organic layers were washed with brine (25 ml), dried (Na ₂ SO ₄ ), filtered and concentrated. Purification by normal phase chromatography using hexane and EtOAc as eluents gave (R)-N-[(1E)-(3-bromophenyl)methylidene]-2-methylpropane-2-sulfinamide (11.8 g, 97%) was obtained as an amber oil.

^1H NMR (400MHz, CDCl ₃ ) δ 8.53 (s, 1H), 8.02 (t, J=1.8 Hz, 1H), 7.74 (dt, J=7.7, 1.2 Hz, 1H), 7.64 (ddd, J=8.0 , 2.0, 1.0 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 1.34 - 1.22 (m, 9H). MS(ESI) m/z: 290 (M+H) ⁺ .

24B. Preparation of (R)-N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide

In a three-necked flask, cooled to 0° C., (R)-N-[(1E)-(3-bromophenyl)methylidene]-2-methylpropane-2-sulfinamide (11.8) in THF (190 ml) g, 40.9 mmol), allyl bromide (3.90 ml, 45.0 mmol) and In (6.58 g, 57.3 mmol) were added. After stirring at room temperature for 18 hours, the reaction was heated to 50° C. for 6 hours and then stirred at room temperature for 18 hours. The reaction mixture was filtered through Celite® and the filtrate was quenched with water (100 ml). A thick, clear, gelatinous material formed in the aqueous layer. The organic portion was extracted with EtOAc (4 x 75 ml). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated to give (R)-N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]. -2-Methylpropane-2-sulfinamide was obtained as a clear oil (9.6 g, 71%).

¹ H NMR (400MHz, CDCl ₃ ) δ 7.48 (t, J=1.8 Hz, 1H), 7.41 (dt, J=7.6, 1.6 Hz, 1H), 7.26 - 7.18 (m, 2H), 5.79 - 5.66 (m , 1H), 5.23 - 5.16 (m, 2H), 4.46 (ddd, J=8.1, 5.6, 2.0 Hz, 1H), 3.69 (s, 1H), 2.63 - 2.53 (m, 1H), 2.53 - 2.40 (m , 1H), 1.23 - 1.19 (m, 9H).

24C. Preparation of tert-butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate

(R)-N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide (9.6 g, 29.1 mmol) was added to concentrated HCl (4 ml). After 3 hours, the reaction was concentrated and the residue was dissolved in DCM (300 ml), cooled to 0° C. and then washed with TEA (16.20 ml, 116 mmol) and Boc ₂ O (6.75 ml, 29.1 mmol) was added. After 18 hours, additional Boc ₂ O (1 g) was added and the reaction was stirred for 4 hours. The reaction was quenched with water (100 ml) and extracted with DCM (3 x 50 ml). The combined organic layers were washed with brine (50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated. Purification by normal phase chromatography using hexane and EtOAc as eluent gave tert-butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (7.3 g , 77%) was obtained as a white solid. MS(ESI) m/z: 326.08 (M+H) ⁺ .

intermediate 25

Preparation of N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate

25A. Preparation of (R)-N-[(1E)-(3-bromo-5-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide

(R)-2-methylpropane-2-sulfinamide (14.96 g, 123 mol) and Cs ₂ CO ₃ in 3-bromo-5-fluorobenzaldehyde (25 g, 123 mol) dissolved in DCM (200 mL). (40.2 g, 123 mol) was added. The reaction mixture was stirred at room temperature overnight. Afterwards, the reaction mixture was filtered and concentrated to give a yellow oil. The yellow oil was purified using a 120 g silica gel ISCO column, eluting with hexanes and EtOAc to give (R)-N-[(1E)-(3-bromo-5-fluorophenyl)methylidene]. -2-Methylpropane-2-sulfinamide (35 g, 93%) was obtained as a yellow oil.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.58 - 8.55 (m, 1H), 8.05 - 7.98 (m, 1H), 7.84 - 7.76 (m, 2H), 1.20 (s, 9H). LCMS m/z 306.1 (M+H).

25B. Preparation of (R)-N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide

N-[(1E)-(3-bromo-5-fluorophenyl)methylidene]-2,2-dimethylpropanamide (35 g, 114 mol) was dissolved in THF (500 mL) in a large three-necked RB flask. Dissolved and flushed with Ar. The solution was cooled to 0° C. and In powder (18.4 g, 160 mol) was added followed by allyl bromide (15.2 g, 126 mol) dropwise. The reaction was stirred at 0° C. for 2 hours, then the ice bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (2 L) and the gelatinous material was filtered through Celite®. The filtrate was concentrated to an oily mass. The crude material was dissolved in water (2 L) and the organics were extracted with EtOAc (4 x 200 mL), dried over MgSO ₄ , filtered and concentrated to give an oil. The oily liquid was purified by silica gel ISCO column and eluting with DCM/MeOH to give (R)-N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-ene- 1-yl]-2-methylpropane-2-sulfinamide (34.9 g, 88% yield) was obtained as a semi-solid material. LCMS m/z 348.2 (M+H).

^1H NMR (500MHz, DMSO-d ₆ ) δ 7.44 - 7.38 (m, 2H), 7.26 - 7.20 (m, 1H), 5.79 - 5.65 (m, 1H), 5.46 - 5.42 (m, 1H), 5.04 - 4.98 (m, 2H), 4.41 - 4.34 (m, 1H), 2.69 - 2.59 (m, 1H), 2.49-2.43 (m, 1H), 1.09 (s, 9H).

25C. Preparation of N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate

(R)-N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]-2-methylpropane-2 dissolved in MeOH (100 mL) To a cooled 0°C solution of -sulfinamide (21.9 g, 100 mol), concentrated HCl (50 mL) was added dropwise, and the reaction was stirred at 0°C for 48 hours. Afterwards, the reaction mixture was concentrated to obtain a white solid mass. The residue was dissolved in water (1 L) and the organics were extracted with EtOAc (2 x 200 mL), dried over MgSO ₄ , filtered and concentrated to a brown oil (11.5 g). The aqueous layer was basified with NaOH and the organics were extracted with EtOAc (2 x 300 mL), dried over MgSO ₄ , filtered and concentrated to a brown oil (18 g). The combined oils were dissolved in DCM (500 mL), to which Boc ₂ O (22 g) was added followed by TEA (15 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by 330 g silica gel ISCO column, eluting with hexane and EtOAc to give a white solid. The white solid was triturated with hexane and the precipitate was collected by filtration to obtain N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate. (29.5 g, 87% yield) was obtained.

intermediate 26

Preparation of N-[(1S)-1-(5-bromopyridin-3-yl)but-3-en-1-yl]carbamate

26A. Preparation of (R)-N-[(1E)-(5-chloropyridin-3-yl)methylidene]-2-methylpropane-2-sulfinamide

5-Bromonicotinaldehyde (6.6 g, 35.9 mmol) was dissolved in DCM (200 mL). Cs ₂ CO ₃ (11.68 g, 35.9 mmol) and (R)-2-methylpropane-2-sulfinamide (4.34 g, 35.9 mol) were added to the solution, and then the reaction mixture was stirred at room temperature overnight. The inorganic portion was filtered and the filtrate was concentrated to give (R)-N-[(1E)-(5-chloropyridin-3-yl)methylidene]-2-methylpropane-2-sulfinamide as an oil ( 10.4 g, 100% yield). LCMS m/z = 291.3.

26B. Preparation of (R)-N-[(1S)-1-(5-chloropyridin-3-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide

(R)-N-[(1E)-(5-chloropyridin-3-yl)methylidene]-2-methylpropane-2-sulfinamide (10.36 g, 35.8 mmol) in THF (150 mL) at 0°C. To the solution, powdered In (5.76 g, 50.2 mmol) was added followed by allyl bromide (3.72 mL, 43.0 mmol). The reaction mixture was sealed and stirred vigorously at 0° C. for 1 hour, then warmed to room temperature and stirred overnight. The reactant gradually changed from light yellow to greenish yellow to dark greenish yellow, and indium metal formed fine particles. LCMS of the greenish black homogeneous solution showed the desired product peak and mass. The solution was filtered through a pad of Celite® and washed with EtOAc. The solution was concentrated to give a yellow solid mass. The solid was dissolved in MeOH (100 mL) and a solution of 4 N HCl in dioxane (25 mL) was added. The resulting solution was stirred at room temperature. After 6 hours, concentrated HCl (1 mL) was added and stirring continued for 1 hour. The reaction mixture was concentrated to give a yellow solid. The solid was dissolved in THF and a mixture of dioxane and DCM (1:1:1, 200 mL). To this solution was added TEA (20 mL) followed by Boc ₂ O (8.1 g, 37.1 mmol) and the reaction mixture was stirred overnight. LCMS confirmed the formation of the desired product. Water (200 mL) was added to the reaction mixture and the mixture was filtered through a pad of Celite® and washed with EtOAc (200 mL). The aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over MgSO ₄ , filtered and concentrated to give a reddish-brown oil. The crude material was purified by 80 g silica gel ISCO column, eluting with hexane and EtOAc. (R)-N-[(1S)-1-(5-chloropyridin-3-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide was prepared as a light yellow semi-solid substance (4.3 g, 36.7% yield). LCMS m/z 327.1 (M+H).

^1H NMR (400MHz, CDCl ₃ ) δ 8.61 - 8.59 (m, 1H), 8.51 - 8.48 (m, 1H), 7.77 - 7.74 (m, 1H), 5.76 - 5.63 (m, 1H), 5.23 - 5.14 ( m, 2H), 5.00 - 4.84 (m, 1H), 4.83 - 4.70 (m, 1H), 2.60 - 2.44 (m, 2H), 1.48 - 1.35 (m, 9H).

intermediate 27

Preparation of tert-butyl N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl] carbamate

27A. Preparation of (R)-N-[(1E)-(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinamide

2-Bromopyridine-4- in a stirred suspension of (R)-2-methylpropane-2-sulfinamide (13.03 g, 108 mmol) and Cs ₂ CO ₃ (52.5 g, 161 mmol) in DCM (400 ml). Carbaldehyde (20 g, 108 mmol) was added over 10 minutes. The reaction mixture was then stirred at room temperature for 18.5 hours. The reaction mixture was concentrated and the residue was diluted with EtOAc (50 ml) and washed with brine (3 x 20 ml). The organic layer was dried over MgSO ₄ , filtered and the filtrate was concentrated. The residue was purified by normal phase chromatography using hexane and EtOAc as eluent to give (R)-N-[(1E)-(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2. -Sulfinamide (27.2 g, 87%) was obtained as a white solid. MS(ESI) m/z: 289-291.0 (M+H) ⁺ .

27B. Preparation of (R)-N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]-2-methylpropane-2-sulfonamide

(R)-N-[(1E)-(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinamide (0.73 g, 2.52 mmol) and In in THF (6 ml) 3-Bromoprop-1-ene (0.458 g, 3.79 mmol) was slowly added to a solution of (0.435 g, 3.79 mmol), and the resulting solution was heated at 60°C for 18 hours. The reaction mixture was cooled, filtered through Celite® and the filtrate was concentrated. To the residue was added EtOAc (100 ml) and 5% aqueous NaHCO ₃ (1 L) and an emulsion formed immediately. The suspension was filtered through paper. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by normal phase chromatography using hexane and EtOAc as eluents to give (R)-N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1- Il]-2-methylpropane-2-sulfonamide (0.62 g, 74%) was obtained as a yellow liquid. MS(ESI) m/z: 331-333.0 (M+H) ⁺ .

27C. Preparation of tert-butyl N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]carbamate

(R)-N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide in MeOH (10 ml) To a solution of (1.38 g, 4.17 mmol) was added 4 N HCl in dioxane (5.21 mL, 20.83 mmol). The reaction mixture was stirred at room temperature for 1.5 hours and then concentrated. ACN (10 ml), TEA (5.8 ml, 41.7 mmol) and Boc ₂ O (1.818 g, 8.33 mmol) were added to the resulting residue. After 18 hours, the reaction mixture was concentrated and the residue was taken up in EtOAc, washed with water, brine, dried over MgSO ₄ , filtered and concentrated. The resulting residue was purified by normal phase chromatography using hexane and EtOAc as eluents to give tert-butyl N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1. -yl] carbamate (0.80 g, 58.7%) was obtained as a light yellow oil. MS(ESI) m/z: 324-326.1 (M+H) ⁺ .

intermediate 28

(9R,13S)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4 Preparation of ,14,16-pentaen-8-one

28A. Preparation of (S)-N-[(1E)-(6-chloropyridin-2-yl)methylidene]-2-methylpropane-2-sulfinamide

Cs ₂ CO ₃ (6.91 g, 21.19 mmol) and 6-chloropicolinaldehyde (2.0 g) in a solution of (S)-2-methylpropane-2-sulfinamide (1.712 g, 14.13 mmol) in DCM (61.4 mL). , 14.13 mmol) was added. The resulting white suspension was stirred at room temperature. After 17 hours, the reaction was filtered. The filtrate was diluted with EtOAc (100 ml) and washed with brine (3 x 50 mL). The organic layer was dried over MgSO ₄ , filtered and concentrated to give (S)-N-[(1E)-(6-chloropyridin-2-yl)methylidene]-2-methylpropane-2-sulfinamide (3.58 g, 100%) was obtained as a yellow oil.

^1H NMR (400MHz, CDCl ₃ ) δ 8.65 (s, 1H), 7.99 - 7.94 (m, 1H), 7.79 (t, J=7.7 Hz, 1H), 7.45 (dd, J=7.9, 0.7 Hz, 1H ), 1.28 (s, 10H).

28B. Preparation of (S)-N-[(1S)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide, and

28C. Preparation of (S)-N-[(1R)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide

(S)-N-[(1E)-(6-chloropyridin-2-yl)methylidene]-2-methylpropane-2-sulfinamide (1.73 g, 7.07 mmol) and In (17.7 ml) in THF (17.7 ml) 3-Bromoprop-1-ene (0.92 g, 10.60 mmol) was slowly added to the mixture. The reaction was heated at 60°C overnight. The reaction mixture was cooled to room temperature, filtered through Celite®, and the filtrate was concentrated. The resulting residue was purified by normal phase chromatography using hexane and EtOAc to give 5.6:1 (S)-N-[(1S)-1-(6-chloropyridin-2-yl)but-3- en-1-yl]-2-methylpropan-2-sulfinamide:(S)-N-[(1R)-1-(6-chloropyridin-2-yl)but-3-en-1-yl] -2-Methylpropane-2-sulfinamide (2.42 g, 58%) was obtained as a brown semi-solid. MS(ESI) m/z: 287.4 (M+H) ⁺ .

28D. (S)-2-methyl-N-[(1R)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en- Preparation of 1-yl]propane-2-sulfinamide (diastereomer A), and

28E. (S)-2-methyl-N-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en- Preparation of 1-yl]propane-2-sulfinamide (diastereomer B)

5.6: ₁ (S)-N-[(1S)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane- in an N 2 flushed pressure vial. 2-Sulfinamide: (S)-N-[(1R)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide (2.18 g, 7.60 mmol), 1-methyl-4-nitro-1H-pyrazole (0.966 g, 7.60 mmol), prepared as described in Intermediate 32A, di(adamant-1-yl)(butyl)phosphine ( 0.954 g, 2.66 mmol), PvOH (0.300 ml, 2.58 mmol), K ₂ CO ₃ (3.62 g, 26.2 mmol), Pd(OAc) ₂ (0.341 g, 1.52 mmol) and DMF (15.2 mL) were added. The vial was purged with Ar. The vial was sealed and heated at 120°C overnight. The reaction mixture was cooled to room temperature, partitioned between water and EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc (3x) and the organic layers were combined and concentrated. The crude product was purified using normal phase chromatography, followed by a second purification by reverse phase chromatography to produce (S)-2-methyl-N-[(1R)-1-[6-(1-methyl-4-nitro). -1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]propane-2-sulfinamide (diastereomer A) (0.275 g, 13%), MS (ESI) m/z: 274.4 (M+H) ⁺ ; and (S)-2-methyl-N-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-ene -1-yl]propane-2-sulfinamide (diastereomer B) (1.2 g, 57%); MS(ESI) m/z: 274.4 (M+H) ⁺ was obtained.

28F. tert-Butyl N-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]car Preparation of Bamate

(1S)-1-(6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-amine (diastereomer B) (1.2 g, 3.18 mmol) was dissolved in MeOH (5 mL) and dioxane (25 ml). 4 N HCl in dioxane (4.8 ml, 19.1 mmol) was added. The reaction was stirred at room temperature for 3 hours and then concentrated. The residue was co-evaporated with toluene, dissolved in DCM (40 mL) and cooled to 0°C. TEA (4.43 mL, 31.8 mmol) was added, followed by BOC ₂ O (0.738 mL, 3.18 mmol). The reaction was stirred at 0° C. for 15 minutes and then allowed to warm to room temperature. After 2 hours, the reaction was diluted with DCM, washed with saturated NaHCO ₃ , brine, and concentrated. Purified by normal phase chromatography, tert-butyl N-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3- En-1-yl]carbamate (393 mg, 33% yield) was obtained as an orange oil. MS(ESI) m/z: 374.5 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.19 (s, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.55 (d, J=7.7 Hz, 1H), 7.38 (d, J=7.7 Hz, 1H), 5.77 - 5.58 (m, 1H), 5.40 (br. s., 1H), 5.13 - 5.01 (m, 2H), 4.92 (d, J=6.8 Hz, 1H), 3.86 (s, 3H), 2.71 - 2.51 (m, 2H), 1.43 (s, 9H).

28G. tert-Butyl N-[(1S)-1-[6-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]car Preparation of Bamate

tert-Butyl N-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-ene in MeOH (6.4 mL) To a solution of -1-yl]carbamate (393 mg, 1.05 mmol) was added AcOH (0.64 mL). The reaction mixture was heated to 45° C., and then Zn powder (206 mg, 3.16 mmol) was added in portions. After 1 hour, additional Zn (198 mg) was added. Upon completion of the reaction, the mixture was cooled to room temperature, partitioned between DCM and saturated NaHCO ₃ and the layers separated. The aqueous layer was extracted with DCM (2x). The organic layers were combined, washed with brine, dried over MgSO ₄ , filtered and concentrated to give tert-butyl N-[(1S)-1-[6-(4-amino-1-methyl-1H-pyrazole- 5-yl)pyridin-2-yl]but-3-en-1-yl]carbamate (343 mg, 95% yield) was obtained as a yellow foam. MS(ESI) m/z: 344.5 (M+H) ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 7.74 (t, J=7.8 Hz, 1H), 7.39 (dd, J=7.8, 0.8 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.14 (d, J =7.7 Hz, 1H), 5.70 (ddt, J=17.1, 10.2, 7.0 Hz, 1H), 5.46 (d, J=6.8 Hz, 1H), 5.13 - 4.99 (m, 2H), 4.89 (d, J= 6.8 Hz, 1H), 4.01 (s, 3H), 2.71 - 2.53 (m, 2H), 1.49 - 1.30 (m, 9H).

28H. tert-Butyl N-[(1S)-1-(6-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyridine- 2-day) Preparation of but-3-en-1-yl]carbamate

tert-Butyl N-[(1S)-1-[6-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl]but-3-ene in EtOAc (3.33 ml) -1-yl]carbamate (343 mg, 0.999 mmol) of (R)-2-methylbut-3-enoic acid (0.150 g, 1.498 mmol) prepared as described in Intermediate 2 in EtOAc (1 ml) The solution was added. The mixture was cooled to 0° C. and pyridine (0.24 ml, 3.0 mmol) was added, followed by a solution of 50% T3P® in EtOAc (1.19 ml, 1.50 mmol). After 2 hours, the reaction was partitioned between saturated NaHCO ₃ and EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (2x). The organic layers were combined, washed with brine and concentrated. Purified by normal phase chromatography, tert-butyl N-[(1S)-1-(6-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazole -5-yl}pyridin-2-yl)but-3-en-1-yl]carbamate (360 mg, 85%) was obtained as a yellow solid. MS(ESI) m/z: 426.5 (M+H) ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 9.35 (br. s., 1H), 8.30 (s, 1H), 7.82 (t, J=7.8 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H) , 7.32 - 7.19 (m, 1H), 6.01 (ddd, J=17.4, 10.0, 7.6 Hz, 1H), 5.78 - 5.57 (m, 1H), 5.35 - 5.04 (m, 5H), 4.91 (br. s. , 1H), 4.06 (s, 3H), 3.26 - 3.06 (m, 1H), 2.81 - 2.54 (m, 2H), 1.54 - 1.30 (m, 12H).

28I. tert-Butyl N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18 ), 2(6),4,10,14,16-hexaen-13-yl] Preparation of carbamate

tert-Butyl N-[(1S)-1-(6-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazole- in EtOAc (25 ml) A solution of 5-yl}pyridin-2-yl)but-3-en-1-yl]carbamate (140 mg, 0.329 mmol) was purged with Ar for 20 min. Second generation Grubbs catalyst (0.112 g, 0.132 mmol) was added and the reaction mixture was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and concentrated. Purification was performed by normal phase chromatography followed by reverse phase chromatography. Fractions containing the desired product were made basic (pH ~8) with saturated NaHCO ₃ and then concentrated. The residue was partitioned between water and EtOAc and the layers were separated. The aqueous layer was extracted with DCM (3x) and EtOAc (3x). The organic layers were combined, washed with brine, dried over MgSO ₄ , filtered and concentrated to give tert-butyl N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7, 18-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (96mg, 66% yield) was obtained. MS(ESI) m/z: 398.2 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 11.12 (br. s., 1H), 8.08 (s, 1H), 7.84 (t, J=7.9 Hz, 1H), 7.39 (dd, J=7.9, 0.7 Hz, 1H), 7.32 - 7.24 (m, 1H), 5.98 - 5.83 (m, 1H), 5.55 (dd, J=15.7, 7.4 Hz, 1H), 5.41 (d, J=6.6 Hz, 1H), 5.04 (m , 1H), 4.10 - 4.03 (m, 3H), 3.15 (quin, J=7.3 Hz, 1H), 2.84 - 2.56 (m, 2H), 1.51 - 1.32 (m, 12H).

28J. tert-butyl N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), Preparation of 2(6),4,14,16-pentaen-13-yl]carbamate, and

28K. tert-Butyl N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-2(6), Preparation of 4-diene-13-yl]carbamate

tert-Butyl N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0 ^2,6 ] in EtOH (4 ml) A solution of octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.096 g, 0.024 mmol) was reacted in the presence of PtO ₂ (20 mg). Hydrogenated at 20 psi H ₂ for 20 hours. The mixture was filtered, washing with MeOH and EtOAc. The filtrate was concentrated and then purified by reverse phase chromatography, and then the fractions were neutralized and extracted to give tert-butyl N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7. ,18-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-2(6),4-dien-13-yl]carbamate (20 mg, 20.4% yield), MS(ESI) m/z : 406.2 (M+H) ⁺ ; and tert-butyl N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18) ,2(6),4,14,16-pentaen-13-yl]carbamate (68 mg, 70.5% yield), MS(ESI) m/z: 400.2 (M+H) ⁺ was obtained.

28L. (9R,13S)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 Preparation of ,14,16-pentaen-8-one

tert-Butyl N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca in DCM (0.5 ml) To a solution of -1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.035 g, 0.088 mmol) was added TFA (0.2 mL, 2.60 mmol). After stirring for 1 hour, the reaction mixture was concentrated to dryness and co-evaporated with CH ₃ CN. The residue was neutralized by dissolving in MeOH, passed through a NaHCO ₃ cartridge (StratoSpheres SPE; 500 mg, 0.90 mmol loading) and the filtrate was concentrated to give (9R,13S)-13-amino-3,9. -Dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (15 mg, 57% yield) was obtained as a clear glass. MS(ESI) m/z: 300.5 (M+H) ⁺ .

intermediate 29

(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), Preparation of 4,14,16-pentaen-8-one

29A. tert-Butyl N-[(1S)-1-[3-fluoro-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl] Preparation of Carbamates

tert-Butyl N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate (0.19 g, 0.552 mmol), 1-methyl-4 -Nitro-1H-pyrazole (0.070 g, 0.552 mmol), di(adamantan-1-yl)(butyl)phosphine (0.059 g, 0.166 mmol), pivalic acid (0.019 ml, 0.166 mmol), K ₂ DMF (1.1 ml) was added to CO ₃ (0.229 g, 1.656 mmol) and the mixture was purged with Ar. Pd(OAc) ₂ (0.025 g, 0.110 mmol) was added and the reaction was heated at 120° C. for 18 hours. The reaction was partitioned between water (15 ml) and EtOAc (30 ml). The aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with brine (15 ml), dried over MgSO ₄ , filtered and concentrated. The residue was purified by normal phase chromatography using hexane and EtOAc as eluents to give tert-butyl N-[(1S)-1-[3-fluoro-5-(1-methyl-4-nitro-1H-pyra). Zol-5-yl)phenyl]but-3-en-1-yl]carbamate (0.123 g, 57%) was obtained as a yellow oil.

^1H NMR (400MHz, CDCl ₃ ) δ 8.23 - 8.17 (m, 1H), 7.22 - 7.16 (m, 1H), 7.10 (s, 1H), 7.01 (dt, J=8.5, 1.9 Hz, 1H), 5.76 - 5.60 (m, 1H), 5.22 - 5.11 (m, 2H), 4.90 (br. s., 1H), 4.78 (br. s., 1H), 3.78 - 3.69 (m, 3H), 2.60 - 2.48 ( m, 2H), 1.41 (br. s., 9H).

29B. tert-Butyl N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]but-3-en-1-yl] Preparation of Carbamates

tert-Butyl N-[(1S)-1-[3-fluoro-5-(1-methyl-4-nitro-1H) dissolved in acetone (5 ml)/water (1 ml), cooled to 0°C. -pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate (0.123 g, 0.315 mmol), NH ₄ Cl (0.084 g, 1.575 mmol) and Zn (0.206 g, 3.15 mmol) ) was added. The ice bath was removed. After 3 hours, the reaction was filtered and the filtrate was partitioned between water (10 ml) and EtOAc (30 ml). The aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with brine (10 ml), dried over MgSO ₄ , filtered and concentrated. The residue was purified by normal phase chromatography using DCM and 0-10% MeOH as eluent to give tert-butyl N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazole -5-yl)-5-fluorophenyl]but-3-en-1-yl]carbamate (0.105 g, 92%) was obtained. MS(ESI) m/z: 361.08 (M+H) ⁺ .

29C. tert-Butyl N-[(1S)-1-(3-fluoro-5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazole-5 Preparation of -1}phenyl)but-3-en-1-yl]carbamate

tert-Butyl N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]but-3- in EtOAc (0.58 ml) To en-1-yl]carbamate (0.105 g, 0.291 mmol) was added (R)-2-methylbut-3-enoic acid (0.035 g, 0.350 mmol) prepared as described in Intermediate 2 in 0.3 ml EtOAc. did. The mixture was cooled to 0° C. and Hunig's base (0.153 ml, 0.874 mmol) followed by a solution of 50% T3P® in EtOAc (0.347 ml, 0.583 mmol) was added. After 4 hours, the reaction was partitioned using saturated NaHCO ₃ (5 ml) and EtOAc (5 ml). The aqueous layer was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (5 ml), dried over MgSO ₄ , filtered and concentrated. The residue was purified by normal phase chromatography using hexane and EtOAc as eluents to give the desired product (53.0 mg, 41%) as a yellow foam. MS(ESI) m/z: 443.5 (M+H) ⁺ .

29D. tert-Butyl N-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

tert-Butyl N-[(1S)-1-(3-fluoro-5-{1-methyl-4-[(2R)-2-methylbut-3-enamido in degassed DCE (10 ml) ]-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamate (0.053 g, 0.120 mmol) was reacted with the second generation Grubbs catalyst (0.041 g, 0.048 mmol). heated to 120° C. in the microwave for 30 min. The reaction mixture was purified directly by normal phase chromatography using hexane and EtOAc as eluents to give tert-butyl N-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3, 4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (27.0 mg , 54%) was obtained as a dark solid. MS(ESI) m/z: 415.4 (M+H) ⁺ .

29E. (9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), Preparation of 4,14,16-pentaen-8-one

tert-Butyl N-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ² in EtOH (3 ml) ^,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.027 g, 0.065 mmol) was mixed with PtO ₂ (5 mg). Hydrogenated for 6 hours in the presence of. The reaction was then filtered through Celite® and the filtrate was purified with tert-butyl N-[(9R,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-tri. Concentrated with azatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (19 mg). The Boc protecting group was removed by dissolving the material in 3 ml of 50% TFA/DCM. After 2 hours, the reaction mixture was concentrated and the residue was taken up in DCM and MeOH and filtered through a basic cartridge. The filtrate was concentrated to (9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18 ),2(6),4,14,16-pentaen-8-one (19 mg, 92%) was obtained as a dark solid. MS(ESI) m/z: 317.4 (M+H) ⁺ .

intermediate 30

(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of ,2(6),4,14,16-pentaen-8-one

30A. Preparation of 1-(difluoromethyl)-4-nitro-1H-pyrazole

Cs ₂ CO ₃ (14.41 g, 44.2 mmol) was suspended in a solution of 4-nitro-1H-pyrazole (5.00 g, 44.2 mmol) and DMF (40 mL). After heating to 120° C. for 5 minutes, solid sodium 2-chloro-2,2-difluoroacetate (13.48 g, 88 mmol) was added in 10 equal portions over 20 minutes. The reaction was complete after 10 minutes of additional heating. The mixture was added to a separatory funnel containing 100 mL water and extracted with Et ₂ O (2 x 50 mL). The combined organic layers were concentrated. Purification by normal phase chromatography elution gradient hexane/EtOAc gave 1-(difluoromethyl)-4-nitro-1H-pyrazole (6.99 g, 42.9 mmol, 97% yield) as a clear, colorless oil.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.58 (s, 1H), 8.22 (s, 1H), 7.39 - 7.05 (t, J = 60 Hz, 1H).

30B. (S)-tert-butyl (1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1- 1) Production of carbamate

N _{2 -} (S)-tert-butyl (1-(4-chloropyridin-2-yl)but-3-en-1-yl)carba prepared as described in Intermediate 23 in 500 mL RBF, flushed. Add mate (10 g, 35.4 mmol), 1-(difluoromethyl)-4-nitro-1H-pyrazole (6.34 g, 38.9 mmol) prepared as described in Intermediate 30A and dioxane (100 mL) did. The solution was bubbled with N ₂ for 5 min, Pd(OAc) ₂ (0.40 g, 1.7 mmol), di(adamantan-1-yl)(butyl)phosphine (1.27 g, 3.5 mmol), K ₂ CO ₃ (14.7 g, 106 mmol) and PvOH (1.08 g, 10.61 mmol) were added. The reaction mixture was bubbled with N ₂ for 5 minutes and then heated to 100° C. for 3 hours. Water (200 mL) was added. The reaction mixture was then extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried over Na ₂ SO ₄ , filtered and concentrated. Purification by normal phase chromatography eluting with a gradient of hexane/EtOAc gave (S)-tert-butyl (1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl )Pyridin-2-yl)but-3-en-1-yl)carbamate (12.91 g, 31.5 mmol, 89% yield) was obtained as a yellowish oil. MS(ESI) m/z: 410.4 [M+H] ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.80 (dd, J=5.1, 0.7 Hz, 1H), 8.36 (s, 1H), 7.34 (s, 1H), 7.31 (dd, J=5.1, 1.5 Hz, 1H ), 7.27 - 6.91 (t, J=58 Hz, 1H), 5.79 - 5.63 (m, 1H), 5.16 - 5.03 (m, 2H), 4.92 (d, J=5.9 Hz, 1H), 2.67 (t, J=6.4 Hz, 2H), 1.46 (br. s., 9H).

30C. (S)-tert-Butyl (1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1- 1) Production of carbamate

(S)-tert-butyl (1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridine in 100 mL, 3-neck RBF in MeOH (12 mL) A solution of -2-yl)but-3-en-1-yl)carbamate (0.78 g, 1.90 mmol) and a solution of NH ₄ Cl (1.02 g, 19 mmol) in water (3 mL) were added. Fe (0.53 g, 9.49 mmol) was added to the solution. The reaction mixture was heated to 65° C. for 3 hours. Water (50 mL) was added. After cooling to room temperature, the mixture was filtered through a pad of Celite® and rinsed with MeOH (200 mL). The filtrate was concentrated. The residue was partitioned between EtOAc (100 mL) and water (100 mL). The organic phase was separated, washed with water (100 mL), brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purified by normal phase chromatography eluting with a gradient of DCM/MeOH, (S)-tert-butyl (1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl )Pyridin-2-yl)but-3-en-1-yl)carbamate (0.585 g, 1.54 mmol, 81% yield) was obtained as an oil. MS(ESI) m/z: 380.1 [M+H] ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.70 (dd, J=5.0, 0.7 Hz, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 7.32 (dd, J=5.1, 1.5 Hz, 1H ), 7.28 - 6.97 (t, J=58 Hz, 1H), 5.80 - 5.66 (m, 1H), 5.65 - 5.53 (m, 1H), 5.13 - 5.03 (m, 2H), 4.87 (br. s., 1H), 3.22 (br. s., 2H), 2.65 (t, J=6.5 Hz, 2H), 1.52 - 1.37 (m, 9H).

30D. tert-Butyl ((S)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl ) Preparation of pyridin-2-yl) but-3-en-1-yl) carbamate

(S)-tert-butyl (1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridine- in a three-neck 250 mL RBF, flushed with N ₂ A solution of 2-yl)but-3-en-1-yl)carbamate (5 g, 13.18 mmol) and EtOAc (50 mL) was added. The solution was cooled to -10°C and (R)-2-methylbut-3-enoic acid (1.72 g, 17.13 mmol), pyridine (4.26 mL, 52.7 mmol), and T3P® (23.54 mL) as described in Intermediate 2. , 39.5 mmol) was added. The cooling bath was removed and the solution was allowed to warm to room temperature and then stirred over a period of 20 hours. Water (30 mL) and EtOAc (30 mL) were added and the mixture was stirred for 30 minutes. The organic phase was separated and the aqueous layer was extracted with EtOAc (30 mL). The combined organic extracts were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated. Purified by normal phase chromatography eluting with a hexane/EtOAc gradient to give tert-butyl ((S)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut- 3-Enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (5.69 g, 12.33 mmol, 94% yield) was obtained. MS(ESI) m/z: 462.2 [M+H] ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.75 (dd, J=5.0, 0.6 Hz, 1H), 8.37 (s, 1H), 7.32 (t, J=59 Hz, 1H), 7.28 (br. s., 1H), 7.20 (s, 1H), 5.97 - 5.85 (m, 1H), 5.78 - 5.65 (m, 1H), 5.56 - 5.44 (m, 1H), 5.28 - 5.19 (m, 2H), 5.12 (d, J=2.0 Hz, 2H), 4.91 - 4.82 (m, 1H), 3.20 - 3.11 (m, 1H), 2.72 - 2.62 (m, 2H), 1.48 - 1.43 (s, 9H), 1.33 (d, J= 6.8 Hz, 3H).

30E. tert-Butyl N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]Octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]Preparation of carbamate

In a 2 L, 3-neck RBF, flushed with N ₂ , tert-butyl ((S)-1-(4-(1-(difluoromethyl)-4-((R)-) in EtOAc (1300 mL) A solution of 2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (3 g, 6.50 mmol) Added. The solution was aerated with Ar for 15 minutes. Second generation Grubbs catalyst (1.38 g, 1.63 mmol) was added in one portion. The reaction mixture was heated at reflux for 24 hours. After cooling to room temperature, the solvent was removed and the residue was purified by normal phase chromatography eluting with a gradient of DCM/MeOH to give tert-butyl N-[(9R,10E,13S)-3-(difluoromethyl )-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16 -Hexaen-13-yl]carbamate (2.13 g, 4.91 mmol, 76% yield) was obtained as a tan solid. MS(ESI) m/z: 434.4 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (d, J=5.1 Hz, 1H), 7.78 (s, 1H), 7.44 - 7.40 (m, 1H), 7.36 (br. s., 1H), 7.27 ( t, J=58 Hz, 1H), 6.87 (s, 1H), 6.49 - 6.39 (m, 1H), 5.78 (s, 1H), 4.80 (br. s., 2H), 3.18 - 3.08 (m, 1H) ), 3.08 - 2.98 (m, 1H), 2.06 - 1.93 (m, 1H), 1.51 (s, 9H), 1.19 (d, J=6.6 Hz, 3H).

30F. tert-Butyl N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

Pd/C (0.60 g, 0.570 mmol) was dissolved in tert-butyl N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3, 4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate ( was added to a 250 mL Parr hydrogenation flask containing a solution of 2.46 g, 5.68 mmol). The flask was purged with N ₂ and pressurized with 55 psi of H ₂ and then stirred for 18 hours. The reaction was filtered through Celite® and concentrated to give tert-butyl N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetra. Azatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (2.17 g, 88% yield) was brown. Obtained as a solid. MS(ESI) m/z: 436.3 [M+H] ⁺ .

^1H NMR (400MHz, DMSO-d ₆ ) δ 9.32 (s, 1H), 8.71 (d, J=5.0 Hz, 1H), 7.96 (t, J=58 Hz, 1H), 7.43 (s, 1H), 7.32 (d, J=4.8 Hz, 1H), 7.22 (d, J=7.3 Hz, 1H), 4.66 (d, J=8.3 Hz, 1H), 2.62 (br. s., 1H), 1.88 (d, J=12.8 Hz, 1H), 1.77 - 1.59 (m, 2H), 1.42 - 1.28 (m, 9H), 1.15 (d, J=18.2 Hz, 2H), 0.83 (d, J=7.0 Hz, 3H).

Example 30G. (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of ,2(6),4,14,16-pentaen-8-one

4 N HCl in dioxane (3.88 mL, 15.5 mmol) was dissolved in tert-butyl N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3 in MeOH (10 mL). ,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (2.25 g, 5.2 mmol) was added to the solution. The reaction was allowed to stir at room temperature for 2 hours. The reaction was cooled in an ice bath and 7 N NH ₃ in MeOH (13.3 mL, 93.0 mmol) was added. After 5 minutes, the reaction was diluted with CH ₂ Cl ₂ (80 mL) and the solid formed was filtered. The filtrate was concentrated to (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca. -1(18),2(6),4,14,16-pentaen-8-one (1.3 g, 3.88 mmol, 75% yield) was obtained. MS(ESI) m/z: 336.3 [M+H] ⁺ .

^1H NMR (400MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 8.71 (d, J=5.0 Hz, 1H), 7.94 (t, J=58 Hz, 1H), 7.85 (s, 1H), 7.40 (s, 1H), 7.32 (d, J=5.0 Hz, 1H), 4.01 (dd, J=10.2, 5.1 Hz, 1H), 2.63 - 2.53 (m, 1H), 1.90 - 1.69 (m, 2H) , 1.53 - 1.36 (m, 2H), 1.16 - 1.00 (m, 1H), 0.85 (d, J=7.0 Hz, 3H).

Intermediate 31

(9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14 ,16-pentaen-8-one, production of hydrochloride

31A. Preparation of tert-butyl N-[(1S)-1-[3-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate

tert-Butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (2 g, 6.13 mmol), 1-methyl-4-nitro-1H- Pyrazole (0.779 g, 6.13 mmol), di(adamantan-1-yl)(butyl)phosphine (0.659 g, 1.839 mmol), pivalic acid (0.213 ml, 1.839 mmol), K ₂ CO ₃ (2.54 g , 18.39 mmol) was added to DMF (9 ml). The mixture was purged with Ar for 10 minutes and Pd(OAc) ₂ (0.275 g, 1.226 mmol) was added. The reaction was heated at 120°C for 15 hours. The reaction was partitioned between water (50 ml) and EtOAc (50 ml), the solution was filtered through paper and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 50 ml). The combined organic layers were washed with brine (50 ml), dried over MgSO ₄ , filtered and concentrated. The residue was purified by normal phase chromatography using hexane and EtOAc as eluent to give (S)-tert-butyl (1-(3-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl )But-3-en-1-yl)carbamate (1.186 g, 3.18 mmol, 51.9% yield) was obtained as a yellow oil. MS(ESI) m/z: 371.1 (MH) ⁺ .

31B. Preparation of tert-butyl N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate

tert-Butyl N-[(1S)-1-[3-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl in acetone (5 ml)/water (1 ml) cooled to 0°C To ]but-3-en-1-yl]carbamate (0.097 g, 0.260 mmol) was added NH ₄ Cl (0.070 g, 1.302 mmol) and Zn (0.170 g, 2.60 mmol). The ice bath was removed. After 3 hours, the reaction was filtered and the filtrate was partitioned between water (10 ml) and EtOAc (30 ml). The aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with brine (10 ml), dried over MgSO ₄ , filtered and concentrated. The residue was purified by normal phase chromatography using DCM and 0-10% MeOH as eluent to give tert-butyl N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazole -5-yl)phenyl]but-3-en-1-yl]carbamate (76.6 mg, 86%) was obtained. MS(ESI) m/z: 343.2 (M+H) ⁺ .

31C. tert-Butyl N-[(1S)-1-(3-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}phenyl) Preparation of but-3-en-1-yl]carbamate

tert-Butyl N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl in EtOAc (0.58 ml) ] To the carbamate (0.076 g, 0.222 mmol) was added (R)-2-methylbut-3-enoic acid (0.027 g, 0.266 mmol) prepared as described in Intermediate 2 in 0.3 mL EtOAc. The mixture was cooled to 0° C. and Hunig's base (0.116 ml, 0.666 mmol) followed by a solution of 50% T3P® in EtOAc (0.264 ml, 0.444 mmol) was added. After 3 hours, the reaction was partitioned using saturated NaHCO ₃ (5 ml) and EtOAc (5 ml). The aqueous layer was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (5 ml), dried over MgSO ₄ , filtered and concentrated. The residue was purified by normal phase chromatography using hexane and EtOAc as eluents to give tert-butyl N-[(1S)-1-(3-{1-methyl-4-[(2R)-2-methylbut- 3-enamido]-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamate (69 mg, 73%) was obtained as a yellow oil. MS(ESI) m/z: 425.2 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.04 (s, 1H), 7.52 - 7.45 (m, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.26 - 7.18 (m, 2H), 7.05 (br . s., 1H), 5.96 - 5.85 (m, 1H), 5.69 (ddt, J=17.0, 10.1, 7.0 Hz, 1H), 5.21 - 5.09 (m, 4H), 4.95 (br. s., 1H) , 4.77 (br. s., 1H), 3.76 (s, 3H), 3.07 (quin, J=7.2 Hz, 1H), 2.61 - 2.48 (m, 2H), 1.45 - 1.38 (m, 9H), 1.30 ( d, J=7.0 Hz, 3H).

31D. tert-butyl N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), Preparation of 2(6),4,10,14,16-hexaen-13-yl]carbamate

tert-Butyl N-[(1S)-1-(3-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyra in degassed DCE (10 ml) A solution of zol-5-yl}phenyl)but-3-en-1-yl]carbamate (0.069 g, 0.163 mmol) was heated to 120° C. in the presence of second generation Grubbs catalyst (0.055 g, 0.065 mmol). Heated in the microwave for 30 minutes. The reaction mixture was directly purified twice by normal phase chromatography using hexane and EtOAc as eluents to obtain the desired tert-butyl N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4, 7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (33 mg, 51.2 %) was obtained as a dark solid. MS(ESI) m/z: 397.1 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 7.61 - 7.52 (m, 1H), 7.46 - 7.40 (m, 1H), 7.33 - 7.25 (m, 1H), 7.20 (d, J=7.5 Hz, 1H), 6.93 (br. s., 1H), 6.83 (s, 1H), 5.63 (ddd, J=15.1, 9.4, 5.6 Hz, 1H), 5.18 (br. s., 1H), 4.89 (dd, J=15.2, 8.8 Hz, 1H), 4.69 (br. s., 1H), 3.93 - 3.86 (m, 3H), 3.09 - 2.99 (m, 1H), 2.69 - 2.58 (m, 1H), 2.17 - 2.08 (m, 1H) ), 1.53 - 1.32 (m, 9H), 1.18 (d, J=6.8 Hz, 3H).

31E. tert-Butyl N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), 4,14,16-pentaen-13-yl] Preparation of carbamate

tert-Butyl N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca in EtOH (5 ml) A solution of -1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.089 g, 0.224 mmol) was hydrogenated at 55 psi for 3 hours under H ₂ atmosphere. I ordered it. The reaction mixture was filtered through a small plug of Celite®, rinsed with EtOH/MeOH/DCM and tert-butyl N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7-tri. Azatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (89 mg, 99%) as a white solid It was obtained as. MS(ESI) m/z: 399.4 (M+H) ⁺ .

^1H NMR (400MHz CDCl ₃ ) δ 7.53 - 7.43 (m, 2H), 7.43 - 7.36 (m, 1H), 7.29 (s, 1H), 6.44 (s, 1H), 4.90 (br. s., 1H) , 4.68 (br. s., 1H), 3.98 (s, 3H), 2.44 (br. s., 1H), 1.93 (d, J=7.7 Hz, 1H), 1.85 - 1.63 (m, 2H), 1.42 (br. s., 9H), 1.28 - 1.19 (m, 2H), 1.07 (d, J=6.8 Hz, 3H), 0.96 (br. s., 1H).

31F. (9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14 , Preparation of 16-pentaen-8-one hydrochloride

tert-Butyl N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] Octadeca-1(18),2( 6),4,14,16-pentaen-13-yl]carbamate (88 mg, 0.221 mmol) was deprotected with 4 N HCl in dioxane (3 ml) for 5 hours. The reaction was concentrated to (9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6) , 4,14,16-pentaen-8-one hydrochloride (70 mg, 95%) was obtained as a dark solid. MS(ESI) m/z: 299.08 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 7.81 (s, 1H), 7.77 - 7.70 (m, 1H), 7.70 - 7.58 (m, 3H), 4.46 (dd, J=12.0, 4.5 Hz, 1H), 4.19 - 4.07 (m, 3H), 3.45 - 3.26 (m, 1H), 2.75 - 2.59 (m, 1H), 2.21 - 2.09 (m, 1H), 1.99 - 1.86 (m, 2H), 1.58 (td, J =14.3, 8.3 Hz, 1H), 1.29 - 1.17 (m, 1H), 1.03 (d, J=6.9 Hz, 3H), 0.94 - 0.82 (m, 1H).

intermediate 32

(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4 Preparation of ,14,16-pentaen-8-one

32A. Preparation of 1-methyl-4-nitro-1H-pyrazole

To a solution of 4-nitro-1H-pyrazole (2.5 g, 22.11 mmol) in THF (50 mL) was added NaH (0.973 g, 24.32 mmol) and the mixture was stirred at room temperature for 5 minutes. CH ₃ I (1.382 mL, 22.11 mmol) was then added to this suspension and stirred at room temperature overnight. The reaction mixture was then diluted with EtOAc (2 x 25 mL) and washed with brine (25 mL). The organic layer was concentrated and then purified using normal phase chromatography to give 1-methyl-4-nitro-1H-pyrazole as a white solid (1.9 g, 80% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.12 (s, 1H), 8.06 (s, 1H), 3.97 (s, 3H).

32B. (S)-tert-Butyl (1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate manufacture of

( _S )-tert-butyl (1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (3.0) prepared as described in Intermediate 23 in an N 2 flushed pressure vial. g, 10.61 mmol), 1-methyl-4-nitro-1H-pyrazole (1.348 g, 10.61 mmol), di(adamant-1-yl)(butyl)phosphine (1.141 g, 3.18 mmol), PvOH (0.369 ml, 3.18 mmol), K ₂ CO ₃ (4.40 g, 31.8 mmol) and DMF (21 mL) were added. The reaction mixture was purged with N ₂ for 5 minutes and Pd(OAc) ₂ (0.476 g, 2.122 mmol) was added. The reaction mixture was purged with N ₂ . The vial was sealed and heated at 120°C for 4 hours. The reaction mixture was cooled to room temperature and partitioned between 10% aqueous LiCl (15 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic layers were washed with brine (15 mL), dried over MgSO ₄ , filtered and concentrated. The crude product was then purified using normal phase chromatography to obtain (S)-tert-butyl (1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl) But-3-en-1-yl)carbamate (1.2 g, 29% yield) was obtained as a brown oil. MS(ESI) m/z: 374.4 (M+H) ⁺ .

32C. (S)-tert-Butyl (1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate manufacture of

(S)-tert-butyl (1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)butyl in MeOH (10 mL) and AcOH (1 mL) A solution of -3-en-1-yl)carbamate (1.2 g, 3.21 mmol) was heated to 40°C. Then, Zn (0.420 g, 6.43 mmol) was slowly added in 3 portions (50:25:25%) to the clear solution and stirred at 40°C for 5 minutes. The reaction mixture was monitored by LCMS and upon completion, the solution was cooled to room temperature and K ₂ CO ₃ and 1 mL water were added. The reaction mixture was stirred for 5 minutes and then filtered through a pad of Celite® and concentrated to give the crude product. The crude product was partitioned between EtOAc (30 mL) and saturated NaHCO ₃ (15 mL). The organic layer was separated and dried over MgSO ₄ . The crude product was purified using normal phase chromatography to give (S)-tert-butyl (1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but- 3-en-1-yl)carbamate (0.88 g, 76% yield) was obtained as a light brown oil. MS(ESI) m/z: 344.4 (M+H) ⁺ .

32D. tert-Butyl ((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridine-2- 1) Preparation of but-3-en-1-yl) carbamate

(S)-tert-butyl (1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but- in a 3-neck 250 mL RBF, flushed with N ₂ A solution of 3-en-1-yl)carbamate (620 mg, 1.805 mmol) and EtOAc (15 mL) was added. The solution was cooled to -10°C and (R)-2-methylbut-3-enoic acid (271 mg, 2.71 mmol), pyridine (0.437 mL, 5.42 mmol) and T3P® (2.149 mL) as prepared in Intermediate 2. , 3.61 mmol) was added. The cooling bath was removed and the solution was allowed to warm to room temperature and then stirred over a period of 20 hours. Water (15 mL) and EtOAc (15 mL) were added and the mixture was stirred for 30 minutes. The organic layer was separated and the aqueous layer was extracted with EtOAc (15 mL). The combined organic extracts were washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated. Purified by normal phase chromatography eluting with a hexane/EtOAc gradient to give tert-butyl ((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido )-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (0.26 g, 34% yield) was obtained. MS(ESI) m/z: 426.5 [M+H] ⁺ .

32E. tert-Butyl N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18 ), 2(6),4,10,14,16-hexaen-13-yl] Preparation of carbamate

Add tert-butyl ((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-) in DCE (18 mL) to a 250 mL, 3-neck RBF, flushed with N ₂ A solution of enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (266 mg, 0.625 mmol) was added. The solution was aerated with Ar for 15 minutes. Second generation Grubbs catalyst (213 mg, 0.250 mmol) was added in one portion. The reaction mixture was heated in the microwave at 120° C. for 30 minutes. After cooling to room temperature, the solvent was removed and the residue was purified by normal phase chromatography eluting with a gradient of DCM/MeOH to give tert-butyl N-[(9R,10E,13S)-3,9-dimethyl-8. -Oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl ]Carbamate (60 mg, 23% yield) was obtained as a tan solid. MS(ESI) m/z: 398.4 [M+H] ⁺ .

32F. tert-butyl N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), Preparation of 2(6),4,14,16-pentaen-13-yl]carbamate

Pd/C (0.016 g, 0.015 mmol) was dissolved in tert-butyl N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetra in EtOH (6 mL). of azatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (60 mg, 0.151 mmol) was added to a 100 mL Parr hydrogenation flask containing the solution. The flask was purged with N ₂ , pressurized with 55 psi of H ₂ and allowed to stir for 5 hours. The reaction was filtered through a pad of Celite® and concentrated to give tert-butyl N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (48 mg, 76% yield) was obtained as a tan solid. MS(ESI) m/z: 400.5 [M+H] ⁺ .

32G. (9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 Preparation of ,14,16-pentaen-8-one

tert-Butyl N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca in DCM (2.5 mL) To a solution of -1(18),2(6),4,14,16-pentaen-13-yl]carbamate (48 mg, 0.120 mmol) was added TFA (0.6 mL, 7.79 mmol), and the reactant was stirred at room temperature for 1.5 hours. The reaction mixture was then concentrated to (9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18) ,2(6),4,14,16-pentaen-8-one bistrifluoroacetate (63 mg, 94% yield) was obtained as a brown solid, which was then dissolved in MeOH (1 mL) to give a clear brown color. A solution was obtained. The solution was added to a pre-rinsed AGILENT® Stratosphere SPE PL-HCO ₃ MP resin cartridge. Gravity filtration eluting with MeOH gave a clear, slightly yellow filtrate. Concentrate to obtain (9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ,4,14,16-pentaen-8-one (25 mg, 93%) was obtained as a light yellow solid. MS(ESI) m/z: 300.4 [M+H] ⁺ .

Intermediate 33

(9R, _13S )-13-amino-3-( ^2H3 )methyl-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of ,2(6),4,14,16-pentaen-8-one

33A. Preparation _of 1-( ^2H3 )methyl-4-nitro-1H-pyrazole

DIAD (5.59 mL, 28.7 mmol) was dissolved in 4-nitro-1H-pyrazole (2.5 g, 22.11 mmol), CD ₃ OD (0.898 mL, 22.11 mmol), and Ph ₃ P (resin bound) in THF (40 ml). ) (8.84 g, 26.5 mmol) was added to the solution and stirred overnight. The reaction was quenched with water, extracted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. _The crude product was purified by normal phase chromatography eluting with a gradient of DCM/MeOH to give 1-( ^2H3 )methyl-4-nitro-1H-pyrazole (1.92 g, 14.76 mmol, 66.7% yield) as a white solid. Obtained. MS(ESI) m/z: 131.0 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.13 (d, J=0.4 Hz, 1H), 8.05 (s, 1H).

33B. tert-Butyl N-[(1S)-1-{4-[1-( ² H ₃ )methyl-4-nitro-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en- 1-day] Preparation of carbamate

(S)-tert-butyl (1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (2.61 g, 9.22 mmol), 1-( ²⁾ in a large microwave vial. H ₃ )methyl-4-nitro-1H-pyrazole (1.0 g, 7.69 mmol), di(adamantan-1-yl)(butyl)phosphine (0.413 g, 1.15 mmol), K ₂ CO ₃ (3.19 g, 23.06 mmol), pivalic acid (0.268 ml, 2.306 mmol) and DMF (15.37 ml) were added. The reaction was purged with Ar for 10 minutes, Pd(OAc) ₂ (0.173 g, 0.769 mmol) was added, the vial was sealed and stirred at 115° C. overnight. The reaction was then partitioned between EtOAc and H ₂ O. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated. The residue was purified by normal phase chromatography eluting with _a hexane/EtOAc gradient to give tert-butyl N-[(1S)-1-{4-[1-( ^2H3 )methyl-4-nitro-1H-pyra. Zol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate (1.49 g, 3.96 mmol, 51.5% yield) was obtained as a lavender foam. MS(ESI) m/z: 377.0 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.77 (d, J=4.8 Hz, 1H), 8.21 (s, 1H), 7.26 (s, 1H), 7.23 (dd, J=5.1, 1.5 Hz, 1H), 5.78 - 5.65 (m, 1H), 5.55 (d, J=6.8 Hz, 1H), 5.14 - 5.03 (m, 2H), 4.89 (d, J=6.8 Hz, 1H), 2.66 (t, J=6.6 Hz) , 2H), 1.44 (s, 9H).

33C. tert-Butyl N-[(1S)-1-{4-[4-amino-1-( ^2H ₃ )methyl-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en- 1-day] Preparation of carbamate

tert-Butyl N-[(1S)-1-{4-[1-( ² H ₃ )methyl-4-nitro-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en- 1-yl]carbamate (1.45 g, 3.85 mmol) was dissolved in acetone (15 ml)/water (3 ml) and cooled to 0°C. NH ₄ Cl (1.030 g, 19.26 mmol) and Zn (2.52 g, 38.5 mmol) were added and the ice bath was removed. After 1 hour, the reaction was filtered and the filtrate was partitioned with water (30 ml) and EtOAc (50 ml). The aqueous layer was extracted with EtOAc (2 x 50 ml). The combined organic layers were washed with brine (20 ml), dried over MgSO ₄ , filtered and concentrated. The residue was purified by normal phase chromatography eluting with a gradient of DCM/MeOH to give tert _- butyl N-[(1S)-1-{4-[4-amino-1-( ^2H3 )methyl-1H-pyra. Zol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate (0.62 g, 46.5%) was obtained. MS(ESI) m/z: 347.2 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.67 (dd, J=5.1, 0.7 Hz, 1H), 7.26 - 7.23 (m, 2H), 7.21 (dd, J=5.1, 1.5 Hz, 1H), 5.79 - 5.66 (m, 1H), 5.58 (d, J=7.3 Hz, 1H), 5.11 - 5.05 (m, 2H), 4.86 (q, J=6.6 Hz, 1H), 2.64 (t, J=6.7 Hz, 2H) , 1.44 (s, 9H).

33D. tert-Butyl N-[(1S)-1-{4-[1-( ² H ₃ )methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazole-5 Preparation of -yl]pyridin-2-yl}but-3-en-1-yl]carbamate

(R)-2-methylbut-3-enoic acid (233 mg, 2.327 mmol), tert-butyl N-[(1S)-1-{4-[4-amino-1-( ²⁾ in EtOAc (17.900 ml) H ₃ )methyl-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate (620 mg, 1.79 mmol), pyridine (0.433 ml, 5.37 mmol) Cooled to -10°C under Ar. T3P® (50 wt% in EtOAc) (2.13 ml, 3.58 mmol) was added dropwise and the reaction mixture was slowly warmed to room temperature. After 3.5 hours, the reaction mixture was diluted with EtOAc, washed with 1.5 MK ₂ HPO ₄ followed by brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was then purified by normal phase chromatography eluting with a gradient of hexane/EtOAc to give tert _- butyl N-[(1S)-1-{4-[1-( ^2H3 )methyl-4-[(2R )-2-methylbut-3-enamido]-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate (529 mg, 1.234 mmol, 69.0 % yield) was obtained as a yellow foam. MS(ESI) m/z: 429.2 (M+H) ⁺ .

33E. tert-Butyl N-[(9R,10E,13S)-3-( ^2H ₃ )methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]Octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]Preparation of carbamate

Five large microwave vials were filled with equal amounts of: tert _- butyl N-[(1S)-1-{4-[1-( ^2H3 )methyl-4- in degassed DCE (90 ml). [(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate (0.51 g, 1.190 mmol) was irradiated at 120° C. for 30 minutes in the presence of the second generation Grubbs catalyst (0.404 g, 0.476 mmol). The reactions were combined, concentrated and the residue purified by normal phase column chromatography eluting with a gradient of hexane/EtOAc to give tert _- butyl N-[(9R,10E,13S)-3-( ^2H3 )methyl-9. -Methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaene -13-yl]carbamate (0.124 g, 26.0%) was obtained as a brown solid. MS(ESI) m/z: 401.2 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.66 (d, J=5.1 Hz, 1H), 7.52 (s, 1H), 7.19 (d, J=4.8 Hz, 1H), 6.80 (s, 1H), 6.37 ( d, J=7.5 Hz, 1H), 5.68 (t, J=11.2 Hz, 1H), 4.82 - 4.63 (m, 2H), 3.12 - 2.93 (m, 2H), 1.93 (q, J=11.1 Hz, 1H) ), 1.48 (s, 9H), 1.15 (d, J=5.9 Hz, 3H).

33F. tert-Butyl N-[(9R,13S)-3-( ^2H ₃ )methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

PtO ₂ (6.80 mg, 0.030 mmol) was dissolved in tert-butyl N-[(9R,10E, _13S)-3-(2H3 ⁾ methyl-9-methyl-8-oxo-3,4 in EtOH (10 ml). ,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.120 g, 0.300 mmol) was added to the stirred solution. The suspension was subjected to H ₂ atmosphere (55 psi) for 1 hour. The catalyst was filtered through a plug of Celite® and the filtrate _{was concentrated to give tert-butyl N-[(9R,13S)-3-(2H3} ⁾ methyl-9-methyl-8-oxo-3,4, 7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.104 g, 86 %) was obtained. MS(ESI) m/z: 403.2 (M+H) ⁺ .

33G. (9R, _13S )-13-amino-3-( ^2H3 )methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of ,2(6),4,14,16-pentaen-8-one

4 M HCl in dioxane (1.62 ml) was dissolved in tert-butyl N-[(9R, _13S)-3-(2H3 ⁾ methyl-9-methyl-8-oxo-3,4, 7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.100 g, 0.248 mmol) was added to the stirred solution and stirred overnight. The reaction mixture was concentrated to dryness and placed under high vacuum. The hydrochloride salt was made free base by dissolving in MeOH, passed through a resin bound NaHCO ₃ cartridge (Stratosphere SPE; 500 mg, 0.90 mmol loading) and the filtrate was concentrated to give (9R,13S)-13-amino. -3-( ^2H3 )methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- ₁ (18),2(6),4,14 , 16-pentaen-8-one was obtained. MS(ESI) m/z: 303.4 (M+H) ⁺ .

Intermediate 34

(9R, _13S )-13-amino-3-( ^2H3 )methyl-9-methyl-3,4,7,17-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of ,2(6),4,14,16-pentaen-8-one

(9R, _13S )-13-amino-3-( ^2H3 )methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18) ,2(6),4,14,16-pentaen-8-one was reacted with (9R,13S)-13-amino-3-c( ^2H3 )methyl-9-methyl-3 as described in _Intermediate 33. ,4,7,15-Tetraazatricyclo[12.3.1.0 ^2,6 ] In a similar manner to octadeca-1(18),2(6),4,14,16-pentaen-8-one, the intermediate (S)-tert-butyl (1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate described in 23 is reacted with (S)-tert-butyl (1) described in intermediate 27. It was prepared by replacing -(2-bromopyridin-4-yl)but-3-en-1-yl)carbamate. MS(ESI) m/z: 303.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.70 (d, J=5.3 Hz, 1H), 7.58 (s, 1H), 7.50 - 7.42 (m, 2H), 4.14 - 4.05 (m, 1H), 2.72 ( td, J=6.7, 3.5 Hz, 1H), 2.06 - 1.94 (m, 2H), 1.65 - 1.50 (m, 2H), 1.41 - 1.26 (m, 1H), 1.02 (d, J=6.8 Hz, 3H) , 0.70 - 0.53 (m, 1H).

intermediate 35

(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2 Preparation of (6),4,14,16-pentaen-8-one

35A. tert-Butyl N-[(1S)-1-{3-[1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl] Preparation of Carbamates

(S)-tert-butyl (1-(3-bromophenyl)but-3-en-1-yl)carbamate (4.0 g, 12.29 mmol) prepared as described in Intermediate 24 in DMF (40.9 ml) ), 1-(difluoromethyl)-4-nitro-1H-pyrazole (2.20 g, 13.49 mmol), di(adamantan-1-yl)(butyl)phosphine (0.659 g, 1.839 mmol) mmol), K ₂ CO ₃ (5.08 g, 36.8 mmol) and pivalic acid (0.427 ml, 3.68 mmol) were added. The resulting solution was purged with Ar for 10 minutes. Pd(OAc) ₂ (0.275 g, 1.226 mmol) was added and the reaction mixture was stirred at 115° C. for 4 hours. The reaction was cooled to room temperature, quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO ₄ ), filtered, and concentrated. The residue was purified by normal phase column chromatography eluting with a heptane/EtOAc gradient to give tert-butyl N-[(1S)-1-{3-[1-(difluoromethyl)-4-nitro-1H- pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate (4.0 g, 80.0%) was obtained. MS(ESI) m/z: 407 (MH) ^- .

35B. tert-Butyl N-[(1S)-1-{3-[4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl] Preparation of Carbamates

tert-Butyl N-[(1S)-1-{3-[1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl] Carbamate (4.0 g, 9.79 mmol) was dissolved in acetone (100 ml)/H ₂ O (24 ml) and then cooled to 0°C. NH ₄ Cl (2.62 g, 49.0 mmol) and Zn (6.40 g, 98 mmol) were added to the solution and the ice bath was removed. After 2 hours, the reaction mixture was filtered and the filtrate was partitioned between water (30 ml) and EtOAc (50 ml). The aqueous layer was extracted with EtOAc (2 x 50 ml). The combined organic phases were washed with brine (20 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography eluting with a gradient of DCM/MeOH to give tert-butyl N-[(1S)-1-{3-[4-amino-1-(difluoromethyl)-1H-pyra. Zol-5-yl]phenyl}but-3-en-1-yl]carbamate (3.33 g, 8.80 mmol, 90%) was obtained as a yellow oil. MS(ESI) m/z: 379.2 (M+H) ⁺ .

35C. tert-Butyl N-[(1S)-1-{3-[1-(difluoromethyl)-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazole-5 Preparation of -yl]phenyl}but-3-en-1-yl]carbamate

tert-Butyl N-[(1S)-1-{3-[4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl]phenyl}but in EtOAc (20 ml) at 0°C. To a solution of -3-en-1-yl]carbamate (3.3 g, 8.72 mmol) was added (R)-2-methylbut-3-enoic acid (1.048) prepared as described in Intermediate 2 in EtOAc (10 ml). g, 10.46 mmol), pyridine (2.116 ml, 26.2 mmol), and T3P®/50% EtOAc (10.38 ml, 17.44 mmol) were added. After 4 hours, the reaction was diluted with EtOAc and washed with a solution of K ₂ HPO ₄ followed by brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by normal phase column chromatography eluting with a gradient of hexane/EtOAc to give tert-butyl N-[(1S)-1-{3-[1-(difluoromethyl)-4-[(2R). -2-methylbut-3-enamido]-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate (3.10 g, 6.73 mmol, 77% yield) was obtained as yellow Obtained as a foam. MS(ESI) m/z: 461.2 (M+H) ⁺ .

35D. tert-Butyl N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

tert-Butyl N-[(1S)-1-{3-[1-(difluoromethyl)-4-[(2R)-2-methylbut-3-enamido in degassed DCM (800 mL) ]-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate (3.0 g, 6.51 mmol) in a solution of second generation Grubbs catalyst (2.212 g, 2.61 mmol) was added, and the reaction was heated to 40°C. After stirring overnight, the mixture was concentrated and the residue was purified by normal phase column chromatography eluting with a gradient of hexane/EtOAc to give tert-butyl N-[(9R,10E,13S)-3-(difluoromethyl )-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexa En-13-yl]carbamate (1.8 g, 63.9%) was obtained. MS(ESI) m/z: 433.2 (M+H) ⁺ .

35E. tert-Butyl N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,14,16-pentaen-13-yl]carbamate

tert-Butyl N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3. 1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (1.3 g, 3.01 mmol) in a solution of PtO ₂ (0.102 g, 0.451 mmol) was added and the reaction was hydrogenated at 55 psi for 4 hours. The reaction mixture was filtered through a plug of Celite® and the filtrate was concentrated to give tert-butyl N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4. ,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.973 g, 74.5% ) was obtained. MS(ESI) m/z: 435.2 (M+H) ⁺ .

35F. (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2 Preparation of (6),4,14,16-pentaen-8-one

tert-Butyl N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ² in DCM (50 ml) ^,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]TFA (5.18 ml, 67.2 mmol) in a solution of carbamate (0.973 g, 2.239 mmol) was added. After 3 hours, the reaction mixture was concentrated to dryness. The residue was partitioned between saturated NaHCO ₃ and EtOAc. The aqueous phase was extracted with EtOAc (3x), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give (9R,13S)-13-amino-3-(difluoromethyl)-9- Methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.619 g, 83 %) was obtained. MS(ESI) m/z: 335 (M+H) ⁺ .

Intermediate 36

(9R, _13S )-13-amino-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2 Preparation of (6),4,14,16-pentaen-8-one

36A. tert-Butyl N-[(1S)-1-{3-[1-( ^2H3 )methyl _- 4-nitro-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl] Preparation of Carbamates

In a solution of tert-butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (3.8 g, 11.65 mmol) in DMF (35 ml), 1- ( ^2H ₃ )methyl-4-nitro-1H-pyrazole (1.667 g, 12.81 mmol), di(adamantan-1-yl)(butyl)phosphine (0.626 g, 1.747 mmol), K ₂ CO ₃ (4.83 g, 34.9 mmol) and pivalic acid (0.406 ml, 3.49 mmol) were added. The reaction was purged with Ar and Pd(OAc) ₂ (0.262 g, 1.165 mmol) was added. The reaction was heated to 115°C. After 4 hours, the reaction was diluted 1:1 EtOAc/water (50 ml) and filtered through paper to remove Pd solids. The filtrate was extracted with EtOAc (2 x 50 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried (MgSO ₄ ), filtered and concentrated. The residue _was purified twice by normal phase chromatography using hexane and EtOAc as eluents to give tert-butyl-N-[(1S)-1-{3-[1-( ^2H3 )methyl-4-nitro- 1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate (1.89 g, 43.2%) was obtained as a brown oil. MS(ESI) m/z: 374.4 (MH) ⁺ .

36B. tert-Butyl N-[(1S)-1-{3-[4-amino-1-( ^2H ₃ )methyl-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl] Preparation of Carbamates

tert-Butyl N-[(1S)-1-{3-[1-( ^2H3 )methyl-4-nitro-1H-pyrazole-5- dissolved in acetone (40 ml)/water (12 _ml ) yl]phenyl}but-3-en-1-yl] To a cooled (0° C.) solution of carbamate (1.89 g, 5.03 mmol) was added NH ₄ Cl (1.346 g, 25.2 mmol) and Zn (3.29 g, 50.3 mmol). mmol) was added. The ice bath was removed and the solution was allowed to warm to room temperature. After 3 hours, the reaction was filtered through paper and the filtrate was partitioned between water (20 ml) and EtOAc (75 ml). The aqueous layer was extracted with EtOAc (2 x 50 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using hexane and EtOAc as eluents followed by DCM/0-10% MeOH to give tert-butyl N-[(1S)-1-{3-[4-amino-1-( ² H ₃ )methyl-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate (0.84 g, 48.3%) was obtained as a light brown foam. MS(ESI) m/z: 346.5 (M+H) ⁺ .

36C. tert-Butyl N-[(1S)-1-{3-[1-( ^2H ₃ )methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazole-5 Preparation of -yl]phenyl}but-3-en-1-yl]carbamate

tert-Butyl N-[(1S)-1-{3-[4-amino-1-( ^2H ₃ )methyl-1H-pyrazol-5-yl]phenyl}but-3- in EtOAc (6 ml) To en-1-yl]carbamate (0.7 g, 2.026 mmol) was added (R)-2-methylbut-3-enoic acid (0.26 g, 2.63 mmol) prepared as described in Intermediate 2 in 1 mL EtOAc. did. The mixture was cooled to 0° C. and pyridine (0.49 ml, 6.08 mmol) followed by a solution of 50% T3P® in EtOAc (2.41 ml, 4.05 mmol). After 1 hour, the reaction was partitioned using saturated NaHCO ₃ (30 ml) and EtOAc (50 ml). The aqueous layer was extracted with EtOAc (2 x 50 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using hexane and EtOAc as eluents to give tert-butyl N-[(1S)-1-{3-[ _1- ( ^2H3 )methyl-4-[(2R)- 2-methylbut-3-enamido]-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate (0.69 g, 81%) was obtained as rose oil. MS(ESI) m/z: 428.5 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.07 - 7.93 (m, 1H), 7.53 - 7.44 (m, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.28 - 7.09 (m, 3H), 5.89 (ddd, J=17.4, 9.9, 7.9 Hz, 1H), 5.76 - 5.60 (m, 1H), 5.25 - 5.11 (m, 4H), 5.07 (d, J=7.0 Hz, 1H), 4.77 (br. s) ., 1H), 3.08 (quin, J=7.2 Hz, 1H), 2.62 - 2.47 (m, 2H), 1.41 (br. s., 9H), 1.30 (s, 3H).

36D. tert-Butyl N-[(9R,10E,13S)-3-( ^2H ₃ )methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

tert-Butyl N-[(1S)-1-{3-[1-( ^2H ₃ )methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazole-5 To a solution of -yl]phenyl}but-3-en-1-yl]carbamate (0.699 g, 1.635 mmol) in degassed DCM (200 ml) was added the second generation Grubbs catalyst (0.555 g, 0.654 mmol). And the resulting solution was heated to 40°C for 24 hours. _The reaction mixture was concentrated and the residue was purified by normal phase chromatography using DCM and 0-10% MeOH as eluent to give tert-butyl N-[(9R,10E,13S)-3-( ^2H3 )methyl. -9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaene -13-yl]carbamate (0.511 g, 78%) was obtained as a dark solid. MS(ESI) m/z: 400.2 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 7.65 - 7.56 (m, 1H), 7.51 - 7.44 (m, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.23 (d, J=7.7 Hz, 1H ), 6.85 (s, 1H), 6.68 (s, 1H), 5.66 (ddd, J=15.2, 9.3, 5.6 Hz, 1H), 5.20 - 5.06 (m, 1H), 4.94 (dd, J=15.3, 8.5 Hz, 1H), 4.78 - 4.66 (m, 1H), 3.08 - 2.99 (m, 1H), 2.71 - 2.58 (m, 1H), 2.23 - 2.12 (m, 1H), 1.43 (br. s., 9H) , 1.25 - 1.19 (m, 3H).

36E. tert-Butyl N-[(9R,13S)-3-( ^2H ₃ )methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,14,16-pentaen-13-yl]carbamate

tert-Butyl N-[(9R,10E,13S)-3-( ^2H ₃ )methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octa PtO ₂ (0.023 g) in EtOH (20 ml) solution of deca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.40 g, 1.001 mmol) , 0.100 mmol) was added. The reaction vessel was purged with H ₂ and then the reaction mixture was hydrogenated at 55 psi. After 1.5 hours under pressure, the reaction mixture was then left to stand under N ₂ overnight. The reaction was then filtered through Celite®, rinsing with DCM and EtOH. The filtrate was concentrated and tert-butyl N-[(9R,13S)-3-( ^2H ₃ )methyl9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.38 g, 95%) was obtained as a brown solid. MS(ESI) m/z: 402.5 (M+H) ⁺ .

36F. (9R, _13S )-13-amino-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2 Preparation of (6),4,14,16-pentaen-8-one

tert-Butyl N-[(9R,13S)-3-( ^2H ₃ )methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.38 g, 0.946 mmol) in dioxane (2 ml) and MeOH (2 ml). Heavy 4 N HCl (2 ml) was added. After 4 hours, the reaction was almost concentrated to dryness. The dry residue was dissolved in MeOH/DCM, filtered through _a 500 mg basic cartridge, and the filtrate was concentrated to give (9R,13S)-13-amino-3-( ^2H3 )methyl-9-methyl-3; 4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.28 g, 98%) as gray Obtained as a solid. MS(ESI) m/z: 302.5 (M+H) ⁺ .

Intermediate 37

(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of ,2(6),4,14,16-pentaen-8-one

37A. (S)-tert-butyl (1-(2-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl)but-3-en-1- 1) Production of carbamate

(S)-tert-butyl (1-(2-bromopyridin-4-yl)but-3-en-1-yl)carbamate (1.5 g) prepared as described in Intermediate 27 in a large microwave vial. , 4.58 mmol), 1-(difluoromethyl)-4-nitro-1H-pyrazole (0.822 g, 5.04 mmol), DMF (15.3 mL), prepared as described in Intermediate 30A, di(adamantane- 1-yl)(butyl)phosphine (0.247 g, 0.688 mmol), K ₂ CO ₃ (1.901 g, 13.75 mmol) and pivalic acid (0.160 mL, 1.375 mmol) were added. The mixture was purged with Ar for 15 minutes. Pd(OAc) ₂ (0.103 g, 0.458 mmol) was added, the vial was sealed and stirred at 115°C. After 4 hours, the reaction was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO ₄ ), filtered, and concentrated to give a dark brown oil. The crude product was purified by normal phase chromatography using heptane and EtOAc as eluents to give (S)-tert-butyl (1-(2-(1-(difluoromethyl)-4-nitro-1H-pyrazole- 5-yl)pyridin-4-yl)but-3-en-1-yl)carbamate (973 mg, 52%) was obtained as an orange solid. MS(ESI) m/z: 410.1 (M+H) ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.73 (d, J=5.2 Hz, 1H), 8.38 (s, 1H), 7.74 (br. s., 1H), 7.63 - 7.48 (m, 1H), 7.44 - 7.37 (m, 1H), 5.69 (ddt, J=17.0, 10.1, 7.0 Hz, 1H), 5.24 - 5.17 (m, 2H), 2.62 - 2.50 (m, 2H), 1.45 (s, 9H).

37B. (S)-tert-butyl (1-(2-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-4-yl)but-3-en-1- 1) Production of carbamate

(S)-tert-butyl (1-(2-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl)but-3-en-1- 1) Carbamate (0.974 g, 2.379 mmol) was dissolved in acetone (15 mL)/water (3 mL), cooled to 0° C., NH ₄ Cl (0.636 g, 11.90 mmol) and Zn (1.555 g, 23.79 mmol) was added. After stirring overnight at room temperature, the reaction mixture was filtered through a plug of Celite® and the filtrate was concentrated. The residue was partitioned using water (30 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (20 mL) and dried (MgSO ₄ ). The product was carried forward as is. MS(ESI) m/z: 380.1 (M+H) ⁺ .

37C. tert-Butyl ((S)-1-(2-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl ) Preparation of pyridin-4-yl) but-3-en-1-yl) carbamate

(S)-tert-butyl (1-(2-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-4-yl)but- in EtOAc (7.91 mL) To a solution of 3-en-1-yl)carbamate (0.900 g, 2.372 mmol) (R)-2-methylbut-3-enoic acid (0.309 g, 3.08 mmol) in EtOAc (0.50 mL) at 0° C. , T3P®/50% EtOAc (2.82 mL, 4.74 mmol) and pyridine (0.576 mL, 7.12 mmol) were added. After 5 hours, the reaction mixture was concentrated and purified by normal phase chromatography using hexane and EtOAc as eluents to give tert-butyl ((S)-1-(2-(1-(difluoromethyl)-4- ((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-4-yl)but-3-en-1-yl)carbamate (680 mg, 62.1 %) was obtained as an oil. MS(ESI) m/z: 462.2 (M+H) ⁺ .

¹ H NMR (500 MHz, CDCl ₃ -d) δ 10.74 (br. s., 1H), 8.60 (s, 1H), 8.57 (d, J=5.2 Hz, 1H), 7.84 (s, 1H), 7.58 - 7.42 (m, 1H), 7.23 - 7.20 (m, 1H), 6.00 (ddd, J=17.3, 10.1, 8.1 Hz, 1H), 5.72 - 5.62 (m, 1H), 5.36 - 5.31 (m, 2H), 5.21 - 5.15 (m, 2H), 3.22 (quin, J=7.2 Hz, 1H), 2.59 - 2.47 (m, 2H), 1.48 - 1.37 (m, 12H).

37D. tert-Butyl N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ]Octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]Preparation of carbamate

Equal portions were placed in three large microwave vials as follows: tert-butyl ((S)-1-() in degassed DCE (61.4 mL) in the presence of second generation Grubbs catalyst (0.500 g, 0.589 mmol). 2-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-4-yl)but-3- En-1-yl)carbamate (0.680 g, 1.473 mmol) was irradiated in a microwave at 120°C for 30 minutes. The reaction mixture was concentrated and purified by normal phase chromatography using hexane and EtOAc as eluents to give tert-butyl N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8- Oxo-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl] Carbamate (158 mg, 24.7%) was obtained as a brown film. MS(ESI) m/z: 434.2 (M+H) ⁺ .

¹ H NMR (500 MHz, CDCl ₃ -d) δ 8.69 (d, J=5.0 Hz, 1H), 8.05 - 7.89 (m, 1H), 7.83 (s, 1H), 7.10 (s, 1H), 6.77 (br s., 1H), 5.73 (ddd, J=15.2, 9.7, 5.1 Hz, 1H), 5.13 - 5.05 (m, 2H), 3.19 - 3.10 (m, 1H), 2.73 (d, J=12.7 Hz, 1H), 2.24 - 2.15 (m, 1H), 1.46 (br. s., 9H), 1.30 - 1.24 (m, 4H).

37E. tert-Butyl N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

PtO ₂ (8.28 mg, 0.036 mmol) was dissolved in tert-butyl N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4, in EtOH (10 mL). 7,17-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.158 g , 0.365 mmol) was added to the solution and treated with H ₂ atmosphere (55 psi). After 3 hours, the catalyst was filtered through a pad of Celite® and the filtrate was concentrated to give tert-butyl N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo- 3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate Obtained. MS(ESI) m/z: 436.1 (M+H) ⁺ .

37F. (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of ,2(6),4,14,16-pentaen-8-one

tert-Butyl N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.159 g, 0.365 mmol) was dissolved in MeOH (0.50 mL) and 4 M in dioxane. Treated with HCl (1.83 mL, 7.30 mmol). After stirring for 14 hours, the reaction mixture was concentrated to dryness. The amine HCl salt was free-basized by dissolving in MeOH and passed through two successive NaHCO ₃ cartridges. The filtrate was concentrated to (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca. -1(18),2(6),4,14,16-pentaen-8-one (0.085 g, 69%) was obtained. MS(ESI) m/z: 336.1 (M+H) ⁺ .

Intermediate 38

Preparation of (10R,14S)-14-amino-10-methyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ]

Nonadeca-1(19),2,4,6,15,17-hexaen-9-one.

38A. {3-[(1S)-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl]phenyl} Preparation of boronic acid

tert-Butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (2.36 g) prepared as described in Intermediate 24 in dioxane (50 ml) , 7.23 mmol), 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (1.798 g, 7.96 mmol), and KOAc ( 2.130 g, 21.70 mmol) was added. The mixture was purged with Ar and PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.295 g, 0.362 mmol) was added. The reaction mixture was heated to 90° C. for 18 hours, then quenched with water (20 ml) and extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with brine (20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was adsorbed onto Celite®, charged to a 100 g reverse phase cartridge, and this was concentrated in 10-100% Solvent B (Solvent A: 90% H ₂ O - 10% MeCN - 0.05% TFA; Solvent B: 90% MeCN - {3-[( _1S )-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl, eluting with a 25 min gradient from 10% H 2 O - 0.05% TFA) ]phenyl}boronic acid was obtained as a tan solid. MS(ESI) m/z: 292.08 (M+H) ⁺ .

38B. Preparation of tert-butyl N-[(1S)-1-[3-(3-aminopyridin-2-yl)phenyl]but-3-en-1-yl]carbamate

{3-[(1S)-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl]phenyl}boronic acid (0.36 g, 1.236 mmol), 2-bromopyridine -3-amine (0.214 g, 1.236 mmol), and 2 M aqueous Na ₂ CO ₃ (3.09 ml, 6.18 mmol) were added to dioxane (8 ml) and purged with a stream of Ar for 10 min. Pd(PPh ₃ ) ₄ (0.143 g, 0.124 mmol) was added, and the reaction mixture was irradiated with a microwave at 120°C for 30 minutes. The reaction was quenched with water (20 ml) and extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with brine (15 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by ISCO 40g column eluting with DCM/0-10% MeOH to give a tan foam (0.352g, 84%). The reaction mixture was filtered, concentrated and the residue was purified by normal phase chromatography using DCM and 0-10% MeOH as eluent to give tert-butyl N-[(1S)-1-[3-(3-amino Pyridin-2-yl)phenyl]but-3-en-1-yl]carbamate (0.352 g, 84%) was obtained as a tan solid. MS(ESI) m/z: 340.5 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.13 (dd, J=4.1, 1.9 Hz, 1H), 7.62 - 7.54 (m, 2H), 7.44 (t, J=7.6 Hz, 1H), 7.26 (s, 2H) ), 7.12 - 7.00 (m, 2H), 5.82 - 5.57 (m, 1H), 5.23 - 5.02 (m, 1H), 4.91 (br. s., 1H), 4.80 (br. s., 1H), 3.82 (br. s., 2H), 2.81 - 2.41 (m, 2H), 1.51 - 1.34 (m, 9H).

38C. tert-Butyl N-[(1S)-1-(3-{3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en-1- [I]Manufacture of carbamate

tert-Butyl N-[(1S)-1-[3-(3-aminopyridin-2-yl)phenyl]but-3-en-1-yl]carbamate (0.334 g, 1.03 mmol) (0° C.) EtOAc (6 mL) solution of (R)-2-methylbut-3-enoic acid (0.135 g, 1.348 mmol), pyridine (0.252 ml, 3.11 mmol) prepared as described in Intermediate 2 in 1 ml EtOAc. ) was added, and a 50% EtOAc solution of T3P® (1.235 ml, 2.074 mmol) was added dropwise. After 1 hour, the reaction was partitioned between saturated NaHCO ₃ (30 ml) and EtOAc (50 ml). The aqueous layer was extracted with EtOAc (2 x 50 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using hexane and EtOAc as eluents to give tert-butyl N-[(1S)-1-(3-{3-[(2R)-2-methylbut-3-enami. do]pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate (0.334 g, 76%) was obtained as a tan solid. MS(ESI) m/z: 428.5 (M+H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (dd, J=8.3, 1.2 Hz, 1H), 8.41 (dd, J=4.6, 1.5 Hz, 1H), 7.60 (br. s., 1H), 7.49 - 7.42 (m, 2H), 7.42 - 7.36 (m, 2H), 7.29 (dd, J=8.4, 4.8 Hz, 1H), 5.84 - 5.62 (m, 2H), 5.16 - 5.02 (m, 4H), 4.92 ( br. s., 1H), 4.80 (br. s., 1H), 3.04 (quin, J=7.3 Hz, 1H), 2.62 - 2.48 (m, 2H), 1.51 - 1.35 (m, 9H), 1.32 - 1.25 (m, 3H).

38D. tert-Butyl N-[(10R,11E,14S)-10-methyl-9-oxo-3,8-diazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7) ,3,5,11,15,17-heptaen-14-yl]Manufacture of carbamate trifluoroacetate

tert-Butyl N-[(1S)-1-(3-{3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en-1- A second generation Grubbs catalyst (0.121 g, 0.142 mmol) was added to a degassed DCE (20 ml) solution of [yl]carbamate (0.15 g, 0.356 mmol), and the resulting solution was heated to 120°C in the microwave for 30 minutes. Heated for minutes. The reaction was concentrated and the residue was subjected to normal phase chromatography followed by reversed phase preparative HPLC (PHENOMENEX® Luna Axia C18 5μ 30 x 100 mm column, 8-min gradient; Solvent A: 30% Purified by (MeOH - 70% H ₂ O - 0.1% TFA; Solvent B: 90% MeOH - 10% H ₂ O - 0.1% TFA) to give tert-butyl N-[(10R,11E,14S)-10-methyl -9-oxo-3,8-diazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl ]Carbamate trifluoroacetate (71 mg, 39%) was obtained as a clear residue. MS(ESI) m/z: 394.5 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.73 (d, J=4.4 Hz, 1H), 8.44 (d, J=7.9 Hz, 1H), 7.99 - 7.89 (m, 1H), 7.69 - 7.59 (m, 1H) ), 7.59 - 7.48 (m, 2H), 7.17 - 7.08 (m, 1H), 5.84 - 5.67 (m, 1H), 4.67 - 4.53 (m, 1H), 4.53 - 4.38 (m, 1H), 3.28 - 3.17 (m, 1H), 2.77 - 2.66 (m, 1H), 2.04 (q, J=11.4 Hz, 1H), 1.46 (br. s., 9H), 1.18 - 1.09 (m, 3H).

38E. tert-Butyl N-[(10R,14S)-10-methyl-9-oxo-3,8-diazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3 , 5,15,17-hexaen-14-yl] Preparation of carbamate

tert-Butyl N-[(10R,11E,14S)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7) ,3,5,11,15,17-heptaen-14-yl]carbamate (0.37 g, 0.940 mmol) (free base prepared as in Example 38D) in EtOH (5 ml). ₂ (21 mg) was added and the reaction mixture was purged with H ₂ and hydrogenated at 20-30 psi for 4 hours. The reaction was filtered through Celite®, and the filtrate was concentrated to give tert-butyl N-[(10R,14S)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate (0.37 g, 99%) was obtained as a dark solid. MS(ESI) m/z: 396.3 (M+H) ⁺ .

38F. (10R,14S)-14-amino-10-methyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2(7),3,5,15,17 -Preparation of hexaen-9-one

tert-Butyl N-[(10R,14S)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2 (7),3 ,5,15,17-hexaen-14-yl]carbamate (0.18 g, 0.455 mmol) was dissolved in 4 N HCl in dioxane (2 ml) and MeOH (2 ml). After 2 hours, the reaction was concentrated and the residue was dissolved in DCM/MeOH and free-based by passing through 500 mg basic cartridges (2x). The filtrate was concentrated to (10R,14S)-14-amino-10-methyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3, 5,15,17-hexaen-9-one (0.11 g, 49%) was obtained as a dark brown film. MS(ESI) m/z: 296.3 (M+H) ⁺ .

Intermediate 39

(10R,14S)-14-amino-10-methyl-3,8,16-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15 , Preparation of 17-hexaen-9-one

39A. Preparation of (S)-tert-butyl (1-(3-amino-[2,4'-bipyridin]-2'-yl)but-3-en-1-yl)carbamate

(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronic acid trifluoroacetate in dioxane (12 ml) To a solution of (0.60 g, 1.477 mmol) was added 2-bromopyridin-3-amine (0.256 g, 1.477 mmol) and 2 M aqueous Na ₂ CO ₃ (3.69 ml, 7.39 mmol). The reaction mixture was purged with a stream of Ar for 10 minutes. Pd(PPh ₃ ) ₄ (0.171 g, 0.148 mmol) was added, and the mixture was irradiated at 120°C for 30 minutes. The reaction was partitioned between water and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by normal phase column chromatography eluting with a gradient of DCM/MeOH to give (S)-tert-butyl (1-(3-amino-[2,4'-bipyridin]-2'-yl)butyl. -3-en-1-yl)carbamate (0.500 g, 99% yield) was obtained as a brown oil. MS(ESI) m/z: 341.1 (M+H) ⁺ .

39B. tert-Butyl ((S)-1-(3-((R)-2-methylbut-3-enamido)-[2,4'-bipyridin]-2'-yl)but-3-ene -1-day) Preparation of carbamate

(R)-2-methylbut-3-enoic acid (0.191 g, 1.909 mmol), prepared as described in Intermediate 2 in EtOAc (14.69 ml), (S)-tert-butyl (1-(3-amino-[ A solution of 2,4'-bipyridin]-2'-yl)but-3-en-1-yl)carbamate (0.500 g, 1.469 mmol), and pyridine (0.356 ml, 4.41 mmol) was incubated at 0 under Ar. After cooling to °C, T3P® (50 wt% in EtOAc) (1.75 ml, 2.94 mmol) was added and the reaction mixture was slowly warmed to room temperature. After stirring overnight, the mixture was diluted with EtOAc, washed with 1.5 MK ₂ HPO ₄ followed by brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was then purified by normal phase chromatography eluting with a gradient of hexane/EtOAc to give tert-butyl ((S)-1-(3-((R)-2-methylbut-3-enamido)- [2,4'-bipyridine]-2'-yl)but-3-en-1-yl)carbamate (0.458 g, 73.8% yield) was obtained as a yellow foam. MS(ESI) m/z: 423.2 (M+H) ⁺ .

39C. tert-Butyl N-[(10R,11E,14S)-10-methyl-9-oxo-3,8,16-triazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2( 7), 3,5,11,15,17-heptaen-14-yl] Carbamate, bis-trifluoroacetate production

tert-Butyl ((S)-1-(3-((R)-2-methylbut-3-ene in degassed DCE (14.79 ml) in the presence of second generation Grubbs catalyst (0.080 g, 0.095 mmol) Amido)-[2,4'-bipyridin]-2'-yl)but-3-en-1-yl)carbamate (100 mg, 0.237 mmol) was irradiated at 120°C for 30 minutes. The reaction mixture was concentrated and purified by reverse phase chromatography to give tert-butyl N-[(10R,11E,14S)-10-methyl-9-oxo-3,8,16-triazatricyclo[13.3.1.0 ^{2 ,7} ]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate, bis-trifluoroacetate (39 mg, 26.5% yield ) was obtained as a brown oil. MS(ESI) m/z: 395.2 (M+H) ⁺ .

39D. tert-Butyl N-[(10R,14S)-10-methyl-9-oxo-3,8,16-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7) ,3,5,15,17-hexaen-14-yl]Manufacture of carbamate

PtO ₂ (2.245 mg, 9.89 μmol) was dissolved in tert-butyl N-[(10R,11E,14S)-10-methyl-9-oxo-3,8,16-triazatricyclo[13.3) in EtOH (10 ml). .1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate, bis-trifluoroacetate (0.039 g, 0.099 mmol) was added to the stirred solution and treated with H ₂ atmosphere (55 psi). After 4 hours, the reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated to give tert-butyl N-[(10R,14S)-10-methyl-9-oxo-3,8,16-triaza. Tricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate was obtained. MS(ESI) m/z: 397.2 (M+H) ⁺ .

39E. (10R,14S)-14-amino-10-methyl-3,8,16-triazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2(7),3,5,15 , Preparation of 17-hexaen-9-one

TFA (0.15 mL, 1.967 mmol) was dissolved in tert-butyl N-[(10R,14S)-10-methyl-9-oxo-3,8,16-triazatricyclo[13.3.1.0 ² in DCM (2.0 ml). ^,7 ]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate (0.039 g, 0.098 mmol) was added to the solution. After stirring for 4 hours, the reaction mixture was concentrated to dryness and placed under high vacuum for 12 hours. The residue was neutralized by dissolution in MeOH, passed through a NaHCO ₃ cartridge (Stratosphere SPE; 500 mg, 0.90 mmol loading), and the filtrate was concentrated to give (10R,14S)-14-amino-10-methyl-3; 8,16-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one was obtained. MS(ESI) m/z: 297.5 (M+H) ⁺ .

intermediate 40

(9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18 ), 2(6),4,14,16-pentaen-8-one production

40A. Preparation of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazole

To a solution of 4-nitro-1H-pyrazole (4.0 g, 35.4 mmol) in DMF (50 mL) was added Cs ₂ CO ₃ (12.68 g, 38.9 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane. (8.35 mL, 38.9 mmol) was added. The resulting suspension was heated to 60° C. for 2 hours. The reaction mixture was then diluted with EtOAc (2 x 25 mL) and washed with 10% LiCl solution (25 mL). The organic layer was concentrated, and the residue was purified using normal phase chromatography to obtain 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazole as a white solid (8.6 g, 85% yield). MS(ESI) m/z: 272.4 (M+H) ⁺ .

40B. (S)-tert-butyl (1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl ) But-3-en-1-yl) Preparation of carbamate

( _S )-tert-butyl (1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (3.0) prepared as described in Intermediate 23 in an N 2 flushed pressure vial. g, 10.61 mmol), 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazole (2.88 g, 10.61 mmol), di( Adamant-1-yl)(butyl)phosphine (0.571 g, 1.59 mmol), PvOH (0.369 ml, 3.18 mmol), K ₂ CO ₃ (4.40 g, 31.8 mmol) and DMF (20 mL) were added. . The vial was purged with N ₂ for 5 minutes and Pd(OAc) ₂ (0.238 g, 1.061 mmol) was added. The reaction mixture was again briefly purged with N ₂ . The vial was sealed and heated at 120°C for 4 hours. The reaction mixture was cooled to room temperature and partitioned between 10% aqueous LiCl (15 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic layers were washed with brine (15 mL), dried over MgSO ₄ , filtered and concentrated. The crude product was purified using normal phase chromatography to obtain (S)-tert-butyl (1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro-1H-pyrazol. Zol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (1.4 g, 25% yield) was obtained as a brown oil. MS(ESI) m/z: 518.3 (M+H) ⁺ .

40C. (S)-tert-butyl (1-(4-(4-amino-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-5-yl)pyridin-2-yl ) But-3-en-1-yl) Preparation of carbamate

(S)-tert-butyl (1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitro- in MeOH (25 mL) and CH ₃ COOH (2.5 mL) A solution of 1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (2.4 g, 4.64 mmol) was heated to 40°C. Zn (0.606 g, 9.27 mmol, 3 parts (50:25:25%)) was then added slowly to the resulting clear solution, and the reaction was stirred at 40°C for 5 minutes. Additional Zn was added to the reaction. The reaction mixture was monitored by LCMS and upon completion, 2.5 g of K ₂ CO ₃ (1 g for 1 mL AcOH) and 2.5 mL water were then added to the cooled reaction mixture. The reaction mixture was then stirred for 5 minutes. The reaction mixture was then filtered over a pad of Celite® and concentrated to give the crude product. The crude product was partitioned between EtOAc (40 mL) and saturated NaHCO ₃ (20 mL). The organic layer was separated, dried over MgSO ₄ , filtered and concentrated. The crude product was purified using normal phase chromatography to obtain (S)-tert-butyl (1-(4-(4-amino-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol. Zol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (1.9 g, 80% yield) was obtained as a light brown oil. MS(ESI) m/z: 488.6 (M+H) ⁺ .

40D. tert-butyl ((S)-1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((R)-2-methylbut-3-enamido) Preparation of -1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

(S)-tert-butyl (1-(4-(4-amino-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyra in a 3-neck 250 mL RBF, flushed with N ₂ Zol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (1.9 g, 3.90 mmol) and EtOAc (25 mL) were added. The solution was cooled to -10°C and (R)-2-methylbut-3-enoic acid (390 mg, 3.90 mmol), pyridine (0.630 mL, 7.79 mmol) and T3P® (3.48 mL) as prepared in Intermediate 2. , 5.84 mmol) was added. The cooling bath was removed and the solution was allowed to warm to room temperature and stirred for 20 hours. Water (20 mL) and EtOAc (20 mL) were added and the mixture was stirred for 30 minutes. The organic phase was separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated. Purified by normal phase chromatography eluting with a gradient hexane/EtOAc to give ((S)-1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((R)- 2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (0.68 g, 28% yield) was obtained. did. MS(ESI) m/z: 570.1 [M+H] ⁺ .

40E. tert-butyl N-[(9R,10E,13S)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-9-methyl-8-oxo-3,4,7,15-tetraaza Preparation of tricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

In a 250 mL, 3-neck RBF, flushed with N ₂ , tert-butyl ((S)-1-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl) in EtOAc (56 mL) -4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (680 mg, 1.193 mmol) of the solution was added. The solution was aerated with Ar for 15 minutes. Second generation Grubbs catalyst (253 mg, 0.298 mmol) was added in one portion. The reaction mixture was heated to reflux overnight. After cooling to room temperature, the solvent was removed and the residue was purified by normal phase chromatography eluting with a gradient of DCM/MeOH to give tert-butyl N-[(9R,10E,13S)-3-{2-[( tert-butyldimethylsilyl)oxy] ethyl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ),4,10,14,16-hexaen-13-yl]carbamate (400 mg, 61% yield) was obtained as a tan solid. MS(ESI) m/z: 542.6 [M+H] ⁺ .

40F. tert-Butyl N-[(9R,13S)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo Preparation of [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

Pd/C (0.078 g, 0.074 mmol) was dissolved in tert-butyl N-[(9R,10E,13S)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-9 in EtOH (20 mL). -Methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaene -13-yl]carbamate (400 mg, 0.738 mmol) was added to a 250 mL Parr hydrogenation flask containing a solution. The flask was purged with N ₂ , pressurized with 55 psi of H ₂ and allowed to stir for 4 hours. The reaction was filtered through a pad of Celite® and concentrated to give tert-butyl N-[(9R,13S)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-9-methyl-8- Oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carba Mate (375 mg, 92% yield) was obtained as a tan solid. MS(ESI) m/z: 544.6 [M+H] ⁺ .

40G. (9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18 ),2(6),4,14,16-pentaen-8-one

tert-Butyl N-[(9R,13S)-3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-9-methyl-8-oxo-3,4,7 in MeOH (5 mL) 15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (375 mg, 0.690 mmol) To the solution was added 4 N HCl (5 mL, 20.0 mmol) in dioxane, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to (9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]Octadeca-1(18),2(6),4,14,16-pentaen-8-one, bis hydrochloride (220 mg, 96% yield) was obtained as a light yellow solid, which was then purified with MeOH ( 4 mL) to give a clear, light yellow solution. The solution was added to a pre-rinsed Agilent® Stratosphere SPE PL-HCO ₃ MP resin cartridge. Gravity filtration eluting with MeOH gave a clear, slightly yellow filtrate. Concentrate (9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1 (18),2(6),4,14,16-pentaen-8-one (170 mg, 96%) was obtained as a light yellow solid. MS(ESI) m/z: 330.5 [M+H] ⁺ .

Intermediate 41

(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), Preparation of 4,14,16-pentaen-8-one

41A. tert-Butyl N-[(1S)-1-[3-fluoro-5-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl] Preparation of Carbamates

tert-Butyl N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate (0.19 g, 0.552) prepared as described in Intermediate 25 mmol) in DMF (1 ml), 1-methyl-4-nitro-1H-pyrazole (0.070 g, 0.552 mmol), di(adamantan-1-yl)(butyl)phosphine (0.059 g, 0.166 mmol), pivalic acid (0.019 ml, 0.166 mmol), K ₂ CO ₃ (0.229 g, 1.656 mmol) and Pd(OAc) ₂ (0.025 g, 0.110 mmol) were added. The reaction mixture was purged with Ar and heated at 120°C. After 18 hours, the reaction was partitioned between water (15 ml) and EtOAc (30 ml). The aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with brine (15 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography, eluting with hexane and EtOAc to give tert-butyl N-[(1S)-1-[3-fluoro-5-(1-methyl-4-nitro-1H-pyrazole- 5-yl)phenyl]but-3-en-1-yl]carbamate was obtained as a yellow oil (0.123 g, 57%).

^1H NMR (400MHz, CDCl ₃ ) δ 8.23 - 8.17 (m, 1H), 7.22 - 7.16 (m, 1H), 7.10 (s, 1H), 7.01 (dt, J=8.5, 1.9 Hz, 1H), 5.76 - 5.60 (m, 1H), 5.22 - 5.11 (m, 2H), 4.90 (br. s., 1H), 4.78 (br. s., 1H), 3.78 - 3.69 (m, 3H), 2.60 - 2.48 ( m, 2H), 1.41 (br. s., 9H).

41B. tert-Butyl N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]but-3-en-1-yl] Preparation of Carbamates

tert-Butyl N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]but-3-en-1-yl] Carbamate (0.123 g, 0.315 mmol) was dissolved in acetone (5 ml)/water (1 ml), cooled to 0° C., NH ₄ Cl (0.084 g, 1.575 mmol) and Zn (0.206 g, 3.15 mmol). ) was added. The ice bath was removed and the reaction mixture was warmed to room temperature. After 3 hours, the reaction was filtered and partitioned between water (10 ml) and EtOAc (30 ml). The aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography, eluting with hexane and EtOAc to give tert-butyl N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)- 5-Fluorophenyl]but-3-en-1-yl]carbamate (0.105 g, 92%) was obtained. MS(ESI) m/z: 361.08 (M+H) ⁺ .

41C. tert-Butyl N-[(1S)-1-(3-fluoro-5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazole-5 Preparation of -1}phenyl)but-3-en-1-yl]carbamate

tert-butyl N-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluorophenyl]but-3-en-1-yl] To the carbamate (0.105 g, 0.291 mmol) was added EtOAc (0.6 ml), (R)-2-methylbut-3-enoic acid (0.035 g, 0.350 mmol) prepared as described in Intermediate 2 in 0.3 ml EtOAc. did. The reaction mixture was cooled to 0°C and a 50% EtOAc solution of T3P® (0.347 ml, 0.583 mmol) and Hunig's base (0.153 ml, 0.874 mmol) was added. After 4 hours, the reaction was partitioned between saturated NaHCO ₃ (5 ml) and EtOAc (5 ml). The aqueous layer was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (5 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography, eluting with hexanes and EtOAc to give tert-butyl N-[(1S)-1-(3-fluoro-5-{1-methyl-4-[(2R)-2- Methylbut-3-enamido]-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamate was obtained as a yellow foam (53 mg, 41%). MS(ESI) m/z: 443.5 (M+H) ⁺ .

41D. tert-Butyl N-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

tert-Butyl N-[(1S)-1-(3-fluoro-5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazole-5 Add second generation Grubbs catalyst (0.041 g, 0.048 mmol) to a degassed DCE (10 ml) solution of -yl}phenyl)but-3-en-1-yl]carbamate (0.053 g, 0.120 mmol). And the reaction mixture was heated in a microwave at 120°C for 30 minutes. The reaction mixture was purified directly by normal phase chromatography, eluting with hexane and EtOAc to give tert-butyl N-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4, 7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate was prepared as a dark solid (27 mg, 54%). MS(ESI) m/z: 415.4 (M+H) ⁺ .

41E. (9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), Preparation of 4,14,16-pentaen-8-one

tert-Butyl N-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca- PtO ₂ (5 mg) was added to a solution of 1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.027 g, 0.065 mmol) in EtOH (3 ml). Added. The reaction mixture was purged with H ₂ and then hydrogenated at 55 psi. After 6 hours, the reaction mixture was filtered through Celite® and concentrated to give 19 mg of a dark solid. MS(ESI) m/z: 417.08 (M+H) ⁺ . The dark solid residue was dissolved in 50% TFA/DCM (3 ml). After 3 hours, the reaction mixture was concentrated and the residue was dissolved in DCM/MeOH, passed through a basic cartridge and concentrated to give (9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3. ,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one dark solid (19 mg, 92% ) was obtained. MS(ESI) m/z: 317.4 (M+H) ⁺ .

Intermediate 42

(9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4 Preparation of ,14,16-pentaen-8-one

42A. tert-Butyl N-[(1S)-1-[2-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]car Preparation of Bamate

In a large microwave vial, tert-butyl N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]carbamate (prepared as described in Intermediate 27) 1.0 g, 3.06 mmol), 1-methyl-4-nitro-1H-pyrazole (0.427 g, 3.36 mmol), dioxane (10 ml), di(adamantan-1-yl)(butyl)phosphine ( 0.164 g, 0.458 mmol), K ₂ CO ₃ (1.267 g, 9.17 mmol) and pivalic acid (0.106 ml, 0.917 mmol) were added. The reaction was purged with Ar. Pd(OAc) ₂ (0.069 g, 0.306 mmol) was added and the reaction was stirred at 100°C. After 4 hours, heating was stopped and the reaction was stirred at room temperature for 72 hours. The reaction was quenched with water (20 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using heptane and EtOAc as eluents to give tert-butyl N-[(1S)-1-[2-(1-methyl-4-nitro-1H-pyrazol-5-yl ) Pyridin-4-yl]but-3-en-1-yl]carbamate (0.62 g, 54%) was obtained as a white foam. MS(ESI) m/z: 374.08 (M+H) ⁺ .

^1H NMR (500MHz, CDCl ₃ ) δ 8.73 (d, J=5.2 Hz, 1H), 8.28 - 8.15 (m, 1H), 7.66 - 7.54 (m, 1H), 7.43 - 7.34 (m, 1H), 5.76 - 5.63 (m, 1H), 5.26 - 5.16 (m, 2H), 4.99 (br. s., 1H), 4.83 (br. s., 1H), 3.97 - 3.85 (m, 3H), 2.66 - 2.46 ( m, 2H), 1.45 (br. s., 9H).

42B. tert-Butyl N-[(1S)-1-[2-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]car Preparation of Bamate

tert-Butyl N-[(1S)-1-[2-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]car To a cooled (0°C) acetone (40 ml)/water (12 ml) solution of bamate (0.62 g, 1.660 mmol) was added NH ₄ Cl (0.444 g, 8.30 mmol) and Zn (1.086 g, 16.60 mmol). did. The ice bath was removed and the reaction was stirred for 18 hours. The reaction was filtered through paper and partitioned using water (20 ml) and EtOAc (75 ml). The aqueous layer was extracted with EtOAc (2 x 50 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using DCM and 0-10% MeOH as eluent to give tert-butyl N-[(1S)-1-[2-(4-amino-1-methyl-1H-pyrazole -5-yl)pyridin-4-yl]but-3-en-1-yl]carbamate (0.46 g, 60%) was obtained. MS(ESI) m/z: 344.5 (M+H) ⁺ .

42C. tert-Butyl N-[(1S)-1-(2-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyridin- 4-day) Preparation of but-3-en-1-yl]carbamate

tert-Butyl N-[(1S)-1-[2-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-4-yl]but-3-en-1-yl]car To bamate (0.6 g, 1.747 mmol) was added (R)-2-methylbut-3-enoic acid (0.189 g, 1.893 mmol) prepared as described in Intermediate 2 in EtOAc (5.8 ml) cooled to 0°C. did. Pyridine (0.424 ml, 5.24 mmol) and a 50% EtOAc solution of T3P® (2.080 ml, 3.49 mmol) were added. After 24 hours, the reaction was partitioned between saturated NaHCO ₃ (10 ml) and EtOAc (20 ml). The aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using hexane and EtOAc as eluents to give tert-butyl N-[(1S)-1-(2-{1-methyl-4-[(2R)-2-methylbut- 3-enamido]-1H-pyrazol-5-yl}pyridin-4-yl)but-3-en-1-yl]carbamate (0.35 g, 47%) was obtained. MS(ESI) m/z: 426.1 (M+H) ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ 10.23 (br. s., 1H), 8.70 - 8.56 (m, 1H), 8.35 (d, J=1.1 Hz, 1H), 7.56 - 7.44 (m, 1H), 7.25 - 7.14 (m, 1H), 6.03 (ddd, J=17.2, 10.2, 8.0 Hz, 1H), 5.39 - 5.17 (m, 3H), 5.03 - 4.63 (m, 2H), 4.14 - 4.08 (m, 3H) ), 3.22 (quin, J=7.2 Hz, 1H), 2.66 - 2.49 (m, 1H), 1.84 - 1.72 (m, 1H), 1.50 - 1.40 (m, 9H), 1.42 - 1.37 (m, 3H), 1.06 - 0.93 (m, 1H).

42D. tert-Butyl N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18 ), 2(6),4,10,14,16-hexaen-13-yl] Preparation of carbamate

tert-Butyl N-[(1S)-1-(2-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl} pyridine- 4-yl) But-3-en-1-yl] To a solution of the carbamate (0.160 g, 0.376 mmol) in degassed DCE (20 ml) was added the second generation Grubbs catalyst (0.096 g, 0.113 mmol) , the reaction mixture was heated in the microwave at 120°C for 30 minutes. The reaction mixture was concentrated and the residue was purified by normal phase chromatography using DCM and MeOH as eluents to give the desired product (29 mg, 19%) as a green film. MS(ESI) m/z: 398.3 (M+H) ⁺ .

^1H NMR (500MHz, CDCl ₃ ) δ 8.71 (d, J=4.7 Hz, 1H), 7.58 (s, 1H), 7.23 (d, J=13.8 Hz, 1H), 7.03 - 6.94 (m, 1H), 6.61 (s, 1H), 5.82 - 5.71 (m, 1H), 5.19 - 5.09 (m, 2H), 4.75 (br. s., 1H), 4.15 - 4.09 (m, 3H), 3.19 - 3.10 (m, 1H), 2.67 (br. s., 1H), 2.28 - 2.15 (m, 2H), 1.54 - 1.39 (m, 9H), 1.34 - 1.28 (m, 3H).

42E. (9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 Preparation of ,14,16-pentaen-8-one

tert-Butyl N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18 ),2(6),4,10,14,16-hexaen-13-yl]PtO ₂ (4 mg) was added to a solution of carbamate (29 mg, 0.073 mmol) in EtOH (3 mL). The reaction mixture was purged with H ₂ and then hydrogenated at 55 psi. After 3 hours, the reaction mixture was filtered through a 0.45 μM filter and concentrated to give a dark solid (MS(ESI) m/z: 400.3 (M+H) ⁺ ). The dark solid residue was dissolved in 4 N HCl in dioxane (1 ml) and MeOH (1 ml). After 3 hours, the mixture was concentrated and the resulting HCl salt was dissolved in DCM/MeOH and passed through a basic cartridge to give (9R,13S)-13-amino-3,9-dimethyl-3,4,7,17- Tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one was obtained as a dark solid (21 mg, 96%). . MS(ESI) m/z: 300.2 (M+H) ⁺ .

Intermediate 43

(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of ,2(6),4,14,16-pentaen-8-one

43A. (S)-tert-butyl (1-(5-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1- 1) Production of carbamate

(S)-tert-butyl (1-(5-bromopyridin-3-yl)but-3-en-1-yl)carbamate (1.0 g) prepared as described in Intermediate 26 in a large microwave vial. , 3.06 mmol), 1-(difluoromethyl)-4-nitro-1H-pyrazole (0.548 g, 3.36 mmol), DMF (10.19 ml), di(adamantan-1-yl)(butyl)phos Pin (0.164 g, 0.458 mmol), K ₂ CO ₃ (1.267 g, 9.17 mmol) and pivalic acid (0.106 ml, 0.917 mmol) were added. The reaction mixture was purged with Ar. After 10 minutes, Pd(OAc) ₂ (0.069 g, 0.306 mmol) was added, the container was sealed, and the mixture was stirred at 115°C. After 4 hours, the reaction was quenched with H ₂ O (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO ₄ ), filtered, and concentrated. The crude material was purified by normal phase chromatography eluting with a gradient of heptane/EtOAc to give (S)-tert-butyl (1-(5-(1-(difluoromethyl)-4-nitro-1H-pyrazole- 5-yl)pyridin-3-yl)but-3-en-1-yl)carbamate (1.25 g, 100%) was obtained. MS(ESI) m/z: 410.2 (M+H) ⁺ .

43B. (S)-tert-butyl (1-(5-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1- 1) Production of carbamate

(S)-tert-butyl (1-(5-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1- 1) Carbamate (1.27 g, 3.10 mmol) was dissolved in acetone (15 ml)/water (3 ml), cooled to 0° C., NH ₄ Cl (0.830 g, 15.51 mmol) and Zn (2.028 g, 31.0 mmol). mmol) was added. The ice bath was removed. After 2 hours, the reaction mixture was filtered and the filtrate was partitioned with water (30 ml) and EtOAc (50 ml). The aqueous layer was extracted with EtOAc (2 x 50 ml). The combined organic phases were washed with brine (20 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography eluting with a gradient of DCM/MeOH to (S)-tert-butyl (1-(5-(4-amino-1-(difluoromethyl)-1H-pyrazole- 5-yl)pyridin-3-yl)but-3-en-1-yl)carbamate (0.720 g, 61.2% yield) was obtained as a solid. MS(ESI) m/z: 380 (M+H) ⁺ .

43C. tert-Butyl ((S)-1-(5-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl ) Preparation of pyridin-3-yl) but-3-en-1-yl) carbamate

(S)-tert-butyl (1-(5-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-3-yl)but- in EtOAc (20 ml) A solution of 3-en-1-yl)carbamate (0.720 g, 1.898 mmol) was cooled to 0° C. and (R)-2-methylbut- prepared as described in Intermediate 2 in EtOAc (10 ml). 3-enoic acid (0.228 g, 2.277 mmol), pyridine (0.460 ml, 5.69 mmol), and T3P® (50wt% in EtOAc) (2.259 ml, 3.80 mmol) were added. After 6 hours, the reaction was partitioned using 1.5 MK ₂ PO ₄ (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO ₄ ), filtered, and concentrated. The residue was purified by normal phase chromatography eluting with a hexane/EtOAc gradient to give tert-butyl ((S)-1-(5-(1-(difluoromethyl)-4-((R)-2- Methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-3-yl)but-3-en-1-yl)carbamate (0.386 g, 44.1% yield) was prepared as a yellow foam. Obtained. MS(ESI) m/z: 462.2 (M+H) ⁺ .

43D. tert-Butyl N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,16-tetraazatricyclo[12.3.1.0 ^2,6 ]Octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]Preparation of carbamate

RBF tert-butyl ((S)-1-(5-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazole-5 -yl)pyridin-3-yl)but-3-en-1-yl)carbamate (0.190 g, 0.412 mmol), pTsOH (0.086 g, 0.453 mmol), degassed DCE (103 ml) were added. The clear yellow solution was warmed to 40° C. and degassed with Ar for 1 hour. Second generation Grubbs catalyst (0.140 g, 0.165 mmol) was added and the reaction was stirred at 40° C. overnight. Additional second generation Grubbs catalyst (0.2 equiv) was added and stirring continued. After stirring for a total of 48 hours, the reaction mixture was cooled to room temperature, washed with saturated NaHCO ₃ , brine, dried over MgSO ₄ , filtered and concentrated. The crude product was purified by normal phase chromatography eluting with a gradient of DCM/MeOH to give tert-butyl N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3. ,4,7,16-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.020 g, 11.2%) was obtained as a brown oil. MS(ESI) m/z: 434.3 (M+H) ⁺ .

43E. tert-Butyl N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,16-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

tert-Butyl N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,16-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.020, 0.046 mmol) in EtOH (3 mL) in PtO ₂ (1.048 mg, 4.61 μmol) was added and the reaction was purged with H ₂ . The reaction mixture was subjected to H ₂ atmosphere (55 psi). After 2 hours, the catalyst was filtered through a plug of Celite® and the filtrate was concentrated to give tert-butyl N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo- 3,4,7,16-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate Obtained. MS(ESI) m/z: 436.2 (M+H) ⁺ .

43F. (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of ,2(6),4,14,16-pentaen-8-one

tert-Butyl N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,16-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.020 g, 0.046 mmol) was dissolved in 4 N HCl in dioxane (0.230 ml, 0.919 mmol). dissolved. A minimal amount of MeOH was added to assist dissolution. After 1 hour, the reaction mixture was concentrated to dryness. The residue was dissolved in MeOH, passed through a NaHCO ₃ cartridge (Stratosphere SPE; 500 mg, 0.90 mmol loading) and concentrated to give (9R,13S)-13-amino-3-(difluoromethyl)-9- Methyl-3,4,7,16-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one was obtained. . MS(ESI) m/z: 336.2 (M+H) ⁺ .

Intermediate 44

Preparation of 6-(2-bromo-5-chlorophenyl)pyrimidin-4-ol

44A. Preparation of 4-(2-bromo-5-chlorophenyl)-6-methoxypyrimidine

To a suspension of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (100 mg, 0.424 mmol) and TsOH·H ₂ O (97 mg, 0.509 mmol) in CH ₃ CN (20 mL) CuBr ₂ (9.48 mg, 0.042 mmol) was added. Then t-butyl nitrite (0.067 mL, 0.509 mmol) was added followed by tetrabutylammonium bromide (274 mg, 0.849 mmol) and the reaction was stirred at room temperature. After 2 hours, water was added and the mixture was extracted with CH ₂ Cl ₂ (2x). The organic layers were combined, dried over MgSO ₄ , filtered and concentrated. Purification by normal phase chromatography gave 4-(2-bromo-5-chlorophenyl)-6-methoxypyrimidine (115 mg, 90% yield) as a white solid. MS(ESI) m/z: 299.2 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.88 (d, J=1.1 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 7.56 (d, J=2.6 Hz, 1H), 7.30 - 7.24 ( m, 1H), 7.04 (d, J=1.1 Hz, 1H), 4.05 (s, 3H).

44B. Preparation of 6-(2-bromo-5-chlorophenyl)pyrimidin-4-ol

6-(2-Bromo-5-chlorophenyl)pyrimidin-4-ol was prepared according to the procedure described in Intermediate 5 for the synthesis of 6-(5-chloro-2-fluorophenyl)pyrimidin-4-ol. Prepared by replacing 6-(5-chloro-2-fluorophenyl)pyrimidin-4-ol with 4-(2-bromo-5-chlorophenyl)-6-methoxypyrimidine. MS(ESI) m/z: 285.2 (M+H) ⁺ .

^1H NMR (400MHz, DMSO-d ₆ ) δ 8.19 (s, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.52 (d, J=2.6 Hz, 1H), 7.41 (dd, J=8.6) , 2.6 Hz, 1H), 6.21 (s, 1H).

Example 45

(9R,13S)-13-(4-{5-chloro-2-[(pyrimidin-2-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- manufacture of onion

(9R,13S)-13-(4-{5-chloro-2-[(pyrimidin-2-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- On, 2 trifluoroacetate (2.75 mg, 19% yield) was reacted with 4-bromopyrimidine hydrochloride (6.78 mg, 0.035 mmol) in a manner similar to the procedure described in Example 314 to 2-bromopyrimidine ( It was prepared by replacing it with 5.51 mg, 0.035 mmol). MS(ESI) m/z: 582.5 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.12 (s, 1H), 8.74 (d, J=5.1 Hz, 1H), 8.46 - 8.42 (m, 3H), 7.73 (s, 1H), 7.66 (d, J=2.6 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.43 (dd, J=8.9, 2.5 Hz, 1H), 6.85 (t, J=5.0 Hz, 1H), 6.79 (s, 1H), 6.06 (dd, J=12.7, 4.3 Hz, 1H), 4.05 (s, 3H), 2.78 - 2.67 (m, 1H), 2.42 - 2.31 (m, 1H), 2.16 - 2.02 (m, 2H), 1.69 - 1.44 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.80 - 0.63 (m, 1H). Analytical HPLC (Method A): RT = 8.33 min, 97.9% purity; Factor XIa Ki = 2,000 nM.

Example 46

Ethyl 2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)- Preparation of 1H-pyrazol-1-yl]acetate

Ethyl 2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^{2 ,6} ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)- 1H-pyrazol-1-yl]acetate trifluoroacetate (3.67 mg, 15% yield) was purified in a similar manner to the procedure described in Example 49, 1-methyl-4-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was reacted with ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro Prepared by replacing rolan-2-yl)-1H-pyrazol-1-yl)acetate (13.67 mg, 0.049 mmol). MS(ESI) m/z: 641.5 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.96 (s, 1H), 8.74 (d, J=5.3 Hz, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 7.56 - 7.52 (m, 2H), 7.51 - 7.49 (m, 3H), 7.45 (s, 1H), 6.41 (s, 1H), 6.00 (dd, J=12.7, 4.1 Hz, 1H), 4.94 (s, 2H), 4.18 (q , J=7.1 Hz, 2H), 4.05 (s, 3H), 2.76 - 2.66 (m, 1H), 2.40 - 2.28 (m, 1H), 2.14 - 2.03 (m, 2H), 1.67 - 1.42 (m, 2H) ), 1.24 (t, J=7.2 Hz, 3H), 1.02 (d, J=6.8 Hz, 3H), 0.80 - 0.65 (m, 1H). Analytical HPLC (Method A): RT = 7.92 min, 99.6% purity; Factor XIa Ki = 25 nM, plasma kallikrein Ki = 7,000 nM.

Example 47

2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H Preparation of -pyrazol-1-yl]acetic acid

2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H -Pyrazol-1-yl]acetic acid trifluoroacetate (8.6 mg, 35% yield) was also isolated from Example 46. MS(ESI) m/z: 613.5 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.94 (s, 1H), 8.75 (d, J=5.3 Hz, 1H), 7.74 (s, 1H), 7.60 (s, 1H), 7.56 - 7.48 (m, 5H), 7.46 (s, 1H), 6.45 (d, J=0.4 Hz, 1H), 6.00 (dd, J=12.5, 4.2 Hz, 1H), 4.90 (s, 2H), 4.05 (s, 3H), 2.75 - 2.66 (m, 1H), 2.33 (tt, J=12.7, 4.5 Hz, 1H), 2.14 - 2.03 (m, 2H), 1.66 - 1.42 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.82 - 0.66 (m, 1H). Analytical HPLC (Method A): RT = 6.68 min, 99.0% purity; Factor XIa Ki = 12 nM, plasma kallikrein Ki = 6,000 nM.

Example 48

2-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)acetonitrile

2-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)acetonitrile trifluoro Acetate (2.2 mg, 11% yield) was purified from 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-) in a manner similar to the procedure described in Example 49. Replacement of 2-yl)-1H-pyrazole with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (9.52 mg, 0.049 mmol) It was manufactured. MS(ESI) m/z: 528.35 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 9.04 (br. s., 1H), 8.74 (d, J=5.2 Hz, 1H), 7.73 (s, 1H), 7.59 - 7.49 (m, 5H), 6.65 (s, 1H), 6.06 (d, J=9.6 Hz, 1H), 4.18 - 4.08 (m, 2H), 4.06 (s, 3H), 2.78 - 2.68 (m, 1H), 2.42 - 2.33 (m, 1H) ), 2.16 - 2.03 (m, 2H), 1.68 - 1.58 (m, 1H), 1.55 - 1.45 (m, 1H), 1.02 (d, J=6.9 Hz, 3H), 0.79 - 0.65 (m, 1H). Analytical HPLC (Method C): RT = 1.46 min, 100% purity; Factor XIa Ki = 16 nM, plasma kallikrein Ki = 850 nM.

Example 49

(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene Preparation of -8-one

(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6 prepared as described in Example 211 in 1,4-dioxane (0.6 ml) and water (0.2 ml) -Oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18) ,2(6),4,14,16-pentaen-8-one (15 mg, 0.024 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- Pd(Ph _{3 P} ) ₄ ( _2.82 mg, 2.440 μmol) was added. The reaction was microwaved at 120°C for 0.5 hours, then cooled to room temperature and concentrated. Purified by reverse phase chromatography, (9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 ,14,16-pentaen-8-one trifluoroacetate (7.9 mg, 47% yield) was obtained as an off-white solid. MS(ESI) m/z: 569.6 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.97 (s, 1H), 8.75 (d, J=5.2 Hz, 1H), 7.73 (s, 1H), 7.59 (s, 1H), 7.55 - 7.52 (m, 2H), 7.50 - 7.45 (m, 3H), 7.33 (s, 1H), 6.40 (d, J=0.6 Hz, 1H), 6.02 (dd, J=12.7, 3.9 Hz, 1H), 4.05 (s, 3H) ), 3.84 (s, 3H), 2.75 - 2.68 (m, 1H), 2.39 - 2.30 (m, 1H), 2.13 - 2.02 (m, 2H), 1.66 - 1.45 (m, 2H), 1.02 (d, J =7.2 Hz, 3H), 0.78 - 0.65 (m, 1H). Analytical HPLC (Method A): RT = 7.01 min, 98.4% purity; Factor XIa Ki = 14 nM, plasma kallikrein Ki = 930 nM.

Example 50

(9R,13S)-13-{4-[5-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine- 1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16- Preparation of pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine- 1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16- Pentaen-8-one trifluoroacetate (11.3 mg, 49% yield) was purified from 1-methyl-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1H-pyrazole was reacted with 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- Prepared by replacing with 2-yl)-1H-pyrazole (10.84 mg, 0.049 mmol). MS(ESI) m/z: 583.5 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.95 (s, 1H), 8.73 (d, J=5.1 Hz, 1H), 7.73 - 7.69 (m, 2H), 7.55 - 7.47 (m, 4H), 7.33 ( d, J=8.4 Hz, 1H), 6.24 (d, J=0.7 Hz, 1H), 5.97 (dd, J=12.7, 4.3 Hz, 1H), 4.05 (s, 3H), 3.81 (s, 3H), 2.76 - 2.65 (m, 1H), 2.39 - 2.28 (m, 1H), 2.13 - 1.97 (m, 2H), 1.90 (s, 3H), 1.66 - 1.42 (m, 2H), 1.01 (d, J=6.8 Hz, 3H), 0.80 - 0.63 (m, 1H). Analytical HPLC (Method A): RT = 7.15 min, 99.6% purity; Factor XIa Ki = 270 nM, plasma kallikrein Ki = 5,200 nM.

Example 51

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10-methyl-4,5,8-triazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3 Preparation of 5,15,17-hexaen-9-one

51A. Preparation of 5-bromopyridazin-4-amine

To tert-butyl N-(5-bromopyridazin-4-yl)carbamate (400 mg, 1.183 mmol) in DCM (15 mL) was added TFA (4.56 mL, 59.2 mmol). The reaction was stirred at room temperature overnight. Concentration gave 5-bromopyridazin-4-amine.trifluoroacetate as a dark brown solid. MS(ESI) m/z: 174.2 (M+H) ⁺ .

51B. (10R,14S)-14-amino-10-methyl-4,5,8-triazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2,4,6,15,17- Preparation of hexaen-9-one

(10R,14S)-14-amino-10-methyl-4,5,8-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2,4,6,15,17- Hexaen-9-one was prepared in a manner similar to the procedure described in Intermediate 38, replacing 2-bromopyridin-3-amine with 5-bromopyridazin-4-amine. MS(ESI) m/z: 297.5 (M+H) ⁺ .

51C. (10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10-methyl-4,5,8-triazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3 Preparation of 5,15,17-hexaen-9-one

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10-methyl-4,5,8-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3 , 5,15,17-hexaen-9-one trifluoroacetate (3.8 mg, 32.7% yield) was purified into (10R,14S)-14-amino-10-methyl in a manner similar to the procedure described in Example 56. -4,5,8-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2,4,6,15,17-hexaen-9-one (4.5 mg, 0.015 mmol) It was manufactured using.

^1H NMR (400MHz, CD ₃ OD) δ 9.42 (s, 1H), 9.14 (s, 1H), 8.82 - 8.77 (m, 1H), 8.42 (s, 1H), 7.90 - 7.84 (m, 1H), 7.81 (s, 1H), 7.77 - 7.72 (m, 1H), 7.70 - 7.65 (m, 1H), 7.65 - 7.61 (m, 2H), 7.30 - 7.24 (m, 1H), 6.45 (d, J=0.7 Hz, 1H), 5.77 (dd, J=12.9, 4.3 Hz, 1H), 2.70 - 2.59 (m, 1H), 2.36 - 2.23 (m, 1H), 2.13 - 2.00 (m, 1H), 2.00 - 1.89 ( m, 1H), 1.67 - 1.35 (m, 2H), 1.26 - 1.13 (m, 1H), 1.07 (d, J=6.8 Hz, 3H). MS(ESI) m/z: 621.0 (M+H) ⁺ . Analytical HPLC (Method A): RT = 8.24 min, purity = 100%; Factor XIa Ki = 5 nM, plasma kallikrein Ki = 18 nM.

Example 52

1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazole -Preparation of 4-carboxylic acid

Ethyl 1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3) in THF (56 μl) .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl} To a solution of phenyl)-1H-pyrazole-4-carboxylate trifluoroacetate (7 mg, 0.011 mmol) was added a solution of LiOH·H ₂ O (4.7 mg, 0.112 mmol) in water (56 μl). . MeOH (1 drop) was added to the resulting cloudy mixture. The reaction was stirred vigorously at room temperature for 3.5 hours. The solution was acidified to pH 5 using 1.0 N HCl and then purified by reverse phase chromatography to give 1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6- Oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyrazole-4-carboxylic acid trifluoroacetate (0.0024 g, 30% yield) was obtained as a white solid. MS(ESI) m/z: 599.1 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ CN) δ 8.73 - 8.66 (m, 2H), 8.17 (s, 1H), 7.94 (s, 1H), 7.81 (d, J=2.2 Hz, 1H), 7.73 - 7.62 ( m, 3H), 7.61 - 7.55 (m, 1H), 7.47 - 7.38 (m, 2H), 6.16 (d, J=0.9 Hz, 1H), 5.98 (dd, J=12.7, 3.9 Hz, 1H), 4.02 (s, 3H), 2.65 (m, 1H), 2.30 - 2.19 (m, 1H), 2.15 - 2.02 (m, 1H), 1.64 - 1.39 (m, 2H), 0.98 (d, J=6.8 Hz, 3H ), 0.61 (m, 1H). Analytical HPLC (Method A): Sunfire, RT = 6.48 min, 99.3% purity; Factor XIa Ki = 5 nM, plasma kallikrein Ki = 2,400 nM.

Example 53

(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-5-chloro-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl Preparation of -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

53A. Preparation of 6-(2-bromo-5-chlorophenyl)-5-chloropyrimidin-4-ol

NCS (20.58 mg, 0.154 mmol) to a suspension of 6-(2-bromo-5-chlorophenyl)pyrimidin-4-ol (40 mg, 0.140 mmol) prepared as described in Intermediate 44 in MeCN (1401 μl) ) was added. The reaction was heated at 60°C for 4 hours. The reaction mixture was concentrated, and the crude residue was purified using normal phase chromatography to give 6-(2-bromo-5-chlorophenyl)-5-chloropyrimidin-4-ol (42 mg, 94%) as white. Obtained as a solid. MS(ESI) m/z: 320.9 (M+H) ⁺ .

53B. (9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-5-chloro-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl Preparation of -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-5-chloro-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (8.3 mg, 41.1% yield) was purified from 6-(2-bromo-5-chlorophenyl)-5-chloropyrimidin-4-ol (8.6 mg, 0.027 mmol) in a manner similar to the procedure described in Example 56. and (9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1() prepared as described in Intermediate 32. It was prepared using 18),2(6),4,14,16-pentaen-8-one (8 mg, 0.027 mmol). MS(ESI) m/z: 603.0 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.99 (s, 1H), 8.75 (d, J=5.1 Hz, 1H), 7.75 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.54 (dd, J=5.1, 1.5 Hz, 1H), 7.50 (s, 1H), 7.45 - 7.38 (m, 2H), 6.06 (dd, J=12.4, 4.1 Hz, 1H), 4.05 (s, 3H), 2.72 (td, J=6.7, 3.1 Hz, 1H), 2.45 - 2.31 (m, 1H), 2.19 - 2.03 (m, 2H), 1.70 - 1.43 (m, 2H), 1.02 (d, J=7.0 Hz, 3H), 0.73 (br. s., 1H). Analytical HPLC (Method A): RT = 9.24 min, 100% purity; Factor XIa Ki = 8 nM, plasma kallikrein Ki = 1,200 nM.

Example 54

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1,3-thiazol-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidine -1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6 ), Preparation of 4,14,16-pentaen-8-one

54A. Preparation of 4-(3-chloro-2-fluoro-6-iodophenyl)-6-methoxypyrimidine

4-Chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (1 g, 3.94 mmol) prepared as described in Intermediate 10C in ACN (26.3 ml) cooled to 0°C. and pTsOH.H ₂ O (1.875 g, 9.86 mmol) was added, followed by NaNO ₂ (0.544 g, 7.88 mmol) and NaI (1.477 g, 9.86 mmol) in water (13.14 ml). After 1 hour, the reaction was warmed to room temperature and stirred overnight. Afterwards, the reaction was partially concentrated to remove ACN, and then NaHCO ₃ was added to neutralize the solution. The resulting solution was extracted with EtOAc. The combined organic layers were washed with saturated Na ₂ S ₂ O ₃ and brine, dried over MgSO ₄ , filtered and concentrated to give a solid which was purified by normal phase chromatography to give 4-(3-chloro-2- Fluoro-6-iodophenyl)-6-methoxypyrimidine (0.934 g, 65% yield) was obtained. MS(ESI) m/z: 365.2 (M+H) ⁺ .

54B. Preparation of 6-(3-chloro-2-fluoro-6-iodophenyl)pyrimidin-4-ol

6-(3-Chloro-2-fluoro-6-iodophenyl)pyrimidin-4-ol for the synthesis of 6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol 4-(3-chloro-2,6-difluorophenyl)-6-methoxypyrimidine prepared as described in Intermediate 4A was reacted with 4-(3-chloro-2) following the procedure as described in Intermediate 4B. It was prepared by replacing -fluoro-6-iodophenyl)-6-methoxypyrimidine. MS(ESI) m/z: 350.8 (M+H) ⁺ .

54C. (9R,13S)-13-[4-(3-chloro-2-fluoro-6-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(di Fluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaene Preparation of -8-one

(9R,13S)-13-[4-(3-chloro-2-fluoro-6-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(di Fluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene -8-one was reacted with 6-(3-chloro-2-fluoro-6-iodophenyl)pyrimidin-4-ol (62.7 mg, 0.179 mmol) and intermediate 30 in a manner similar to the procedure described in Example 56. (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa prepared as described in It was prepared using deca-1(18),2(6),4,14,16-pentaen-8-one (60 mg, 0.179 mmol). MS(ESI) m/z: 667.1 (M+H) ⁺ .

54D. (9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1,3-thiazol-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidine -1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6 ), Preparation of 4,14,16-pentaen-8-one

Microwave tube with (9R,13S)-13-[4-(3-chloro-2-fluoro-6-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]- 3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14, 16-pentaen-8-one (20 mg, 0.030 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (9.47 mg , 0.045 mmol), K ₃ PO ₄ (29.9 μl, 0.090 mmol) and THF (299 μl) were added. The solution was bubbled through Ar for a few minutes, then (DtBPF)PdCl ₂ (0.974 mg, 1.495 μmol) was added. The reaction was sealed and heated at 90°C overnight. The solution was cooled to room temperature, Ar was again bubbled through the solution for a few minutes and additional 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Thiazole (9.47 mg, 0.045 mmol) and Pd(PPh ₃ ) ₄ (3.46 mg, 2.99 μmol) were added. The solution was heated in the microwave at 120°C for 30 minutes. The solution was then filtered and the residue was purified by reverse phase chromatography to (9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1,3-thiazole-5- 1) phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.67 mg, 2.9%) was obtained.

¹ H NMR (400MHz, CD ₃ OD) δ 9.02 (s, 1H), 8.95 (s, 1H), 8.77 (d, J=5.1 Hz, 1H), 7.80 (s, 1H), 7.74 (s, 1H) , 7.72 - 7.60 (m, 3H), 7.59 - 7.50 (m, 2H), 7.46 (dd, J=8.4, 1.3 Hz, 1H), 6.55 (s, 1H), 6.05 (dd, J=12.9, 4.3 Hz) , 1H), 2.71 (dt, J=6.6, 3.3 Hz, 1H), 2.40 - 2.26 (m, 1H), 2.12 - 1.97 (m, 2H), 1.70 - 1.41 (m, 2H), 1.00 (d, J =7.0 Hz, 3H), 0.66 (br. s., 1H). MS(ESI) m/z: 625.9 (M+H) ⁺ . Analytical HPLC (Method A): RT = 8.51 min, purity = 96.4%; Factor XIa Ki = 1.7 nM, plasma kallikrein Ki = 230 nM.

Example 55

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 Preparation of 14,16-pentaen-8-one trifluoroacetate

55A. Preparation of 1-methyl-4-nitro-1H-pyrazole

To a solution of 4-nitro-1H-pyrazole (2.5 g, 22.11 mmol) in THF (50 mL) was added NaH (0.973 g, 24.32 mmol) and the mixture was stirred at room temperature for 5 minutes. MeI (1.382 mL, 22.11 mmol) was added to this suspension, and the resulting solution was stirred at room temperature overnight. The reaction mixture was then diluted with EtOAc and washed with brine. The organic layer was concentrated and then purified using normal phase chromatography to give 1-methyl-4-nitro-1H-pyrazole as a white solid (1.9 g, 80%).

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.12 (s, 1H), 8.06 (s, 1H), 3.97 (s, 3H).

55B. (S)-tert-Butyl (1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate manufacture of

(S)-tert-butyl 1-(4-chloropyridin-2-yl)but-3-enylcarbamate (3.0 g, 10.61 mmol), prepared as described in Intermediate 23, in a pressure vial. 4-nitro-1H-pyrazole (1.348 g, 10.61 mmol), di(adamant-1-yl)(butyl)phosphine (1.141 g, 3.18 mmol), pivalic acid (0.369 mL, 3.18 mmol) and K ₂ CO ₃ (4.40 g, 31.8 mmol) was added. DMF (21 mL) was added to the mixture and the vial was purged and evacuated (3x) with Ar. Pd(OAc) ₂ (0.476 g, 2.122 mmol) was added to this mixture. The vial was sealed and heated at 120°C overnight. The reaction mixture was cooled to room temperature, filtered, and partitioned between 10% aqueous LiCl (15 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic layers were washed with brine (15 mL), dried over MgSO ₄ , filtered and concentrated. The crude product was then purified using normal phase chromatography to obtain (S)-tert-butyl (1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl) But-3-en-1-yl)carbamate (1.2 g, 29% yield) was obtained as a brown oil. MS(ESI) m/z: 374.4 (M+H) ⁺ .

55C. (S)-tert-Butyl (1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate manufacture of

(S)-tert-butyl (1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl in MeOH (10 mL) and CH ₃ COOH (1 ml) )But-3-en-1-yl)carbamate (1.2 g, 3.21 mmol) was heated to 60°C. Zn (0.420 g, 6.43 mmol) was then added slowly to the clear solution and the solution was allowed to stir at 60° C. for an additional 15 minutes. The reaction mixture was then filtered through Celite® and concentrated to give the crude product. The crude product was then purified using normal phase chromatography to obtain (S)-tert-butyl (1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl) But-3-en-1-yl)carbamate (0.88 g, 76% yield) was obtained as a light brown oil. MS(ESI) m/z: 344.4 (M+H) ⁺ .

55D. tert-Butyl ((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridine-2- 1) Preparation of but-3-en-1-yl) carbamate

(R)-4-benzyl-3-((R)-2-methylbut-3-enoyl)oxazolidine-2 prepared as described in Intermediate 2A in EtOAc (40 mL) at -10°C under Ar. -one (385 mg, 3.84 mmol), (S)-tert-butyl (1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3 To a solution of -en-1-yl)carbamate (880 mg, 2.56 mmol) and pyridine (0.620 mL, 7.69 mmol) was added dropwise T3P® (50 wt% in EtOAc) (3.05 mL, 5.12 mmol). The reaction mixture was stirred at -10°C and allowed to slowly warm to room temperature. The reaction mixture was stirred at room temperature for 2 hours, then diluted with EtOAc and washed with saturated aqueous NaHCO ₃ and brine. The organic layers were combined together, dried over MgSO ₄ , filtered and concentrated. The crude product was then purified using normal phase chromatography to obtain tert-butyl ((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)- 1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (0.6 g, 52% yield) was obtained as a yellow oil. MS(ESI) m/z: 426.5 (M+H) ⁺ .

55E. tert-Butyl N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18 ), 2(6),4,10,14,16-hexaen-13-yl] Preparation of carbamate

tert-Butyl ((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazole-5- in DCE (18 mL) A solution of 1)pyridin-2-yl)but-3-en-1-yl)carbamate (600 mg, 1.410 mmol) was purged with Ar (3x). Second generation Grubbs catalyst (480 mg, 0.564 mmol) was added and Ar was bubbled back into the reaction mixture and evacuated (3x). The reaction mixture was then heated in a microwave vial at 120° C. for 30 minutes. The reaction mixture was then concentrated and the crude residue was purified using normal phase chromatography to give tert-butyl N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7, 15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (118 mg, 20 % yield) was obtained as a brown oil. MS(ESI) m/z: 398.5 (M+H) ⁺ .

55F. tert-butyl N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), Preparation of 2(6),4,14,16-pentaen-13-yl]carbamate

tert-Butyl N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] in EtOH (12 mL) Pd/C (31.6 mg, 31.6 mg, 0.030 mmol) was added and the reaction mixture was stirred under 55 psi of H ₂ for 5 hours. The reaction mixture was then filtered through Celite® and concentrated to give tert-butyl N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[ 12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (92 mg, 72%) was obtained as a brown oil. MS(ESI) m/z: 400.4 (M+H) ⁺ .

55G. (9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 ,14,16-pentaen-8-one, production of dihydrochloride

tert-Butyl N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca in MeOH (3 mL) A solution of -1(18),2(6),4,14,16-pentaen-13-yl]carbamate (92 mg, 0.230 mmol) in 4 M HCl (3 mL, 12 mmol) in dioxane. was added, and the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to (9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2. (6),4,14,16-pentaen-8-one dihydrochloride (86 mg) was obtained as a yellow solid. MS(ESI) m/z: 300.4 (M+H) ⁺ .

55H. (9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4 Preparation of 14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 , 14,16-pentaen-8-one trifluoroacetate was reacted with (9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraaza according to the procedure described in Example 56. tricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one dihydrochloride and 6-(prepared as described in Intermediate 7 It was prepared using 3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol. MS(ESI) m/z: 574.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.82 (s, 1H), 8.73 (d, J=5.3 Hz, 1H), 8.19 (d, J=1.1 Hz, 1H), 7.85 (dd, J=8.6, 7.7 Hz, 1H), 7.78 (d, J=1.1 Hz, 1H), 7.70 (s, 1H), 7.56 - 7.50 (m, 2H), 7.49 (s, 1H), 6.53 (s, 1H), 5.98 ( dd, J=12.8, 4.2 Hz, 1H), 4.05 (s, 3H), 2.70 (td, J=6.7, 3.2 Hz, 1H), 2.27 (ddt, J=12.7, 8.5, 4.3 Hz, 1H), 2.14 - 1.92 (m, 2H), 1.66 - 1.53 (m, 1H), 1.46 (ddd, J=15.1, 10.0, 5.3 Hz, 1H), 1.00 (d, J=7.0 Hz, 3H), 0.68 (m., 1H). Analytical HPLC (Method A): RT = 6.41 min, purity = 93%; Factor XIa Ki = 1.0 nM, plasma kallikrein Ki = 24 nM.

Example 56

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one trifluoroacetate

6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl prepared as described in Intermediate 15 in anhydrous ACN (0.5 mL) } DBU (15 mL, 0.100 mmol) was added to the scintillation vial containing pyrimidin-4-ol (22.8 mg, 0.067 mmol), HATU (33.0 mg, 0.087 mmol). After 30 min, (9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraaza prepared as described in intermediate 32 in 0.5 ml CH ₃ CN and DMF (0.1 ml) A solution of tricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (20 mg, 0.067 mmol) was added. The resulting solution was stirred at room temperature for 2 hours and then purified by reverse phase chromatography to obtain (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H- 1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraaza Tricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (26.98 mg, 53.1% yield) was obtained as a white solid. It was obtained as. MS(ESI) m/z: 624.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) d 8.81 (d, J=0.7 Hz, 1H), 8.75 (s, 1H), 8.70 (d, J=5.3 Hz, 1H), 7.89 (d, J=2.4 Hz) , 1H), 7.77 - 7.72 (m, 1H), 7.72 - 7.66 (m, 2H), 7.53 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.43 (s, 1H), 6.02 - 5.93 (m, 1H), 4.04 (s, 3H), 2.70 (td, J=6.7, 3.3 Hz, 1H), 2.27 (tt, J=12.7, 4.4 Hz, 1H), 2.12 - 1.94 (m, 2H), 1.66 - 1.52 (m, 1H), 1.45 (ddd, J=15.0, 9.8, 5.0 Hz, 1H), 1.00 (d, J=7.0 Hz, 3H), 0.69 (br. s., 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) d -62.54 (s), -77.44 (s). Analytical HPLC (Method A): RT = 11.02 min, purity = 96.7%; Factor XIa Ki = 1.4 nM, plasma kallikrein Ki = 24 nM.

Example 57

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6), Preparation of 4,14,16-pentaen-8-one trifluoroacetate

57A. Preparation of 2-ethylbut-3-enoic acid

To the dry flask was added 2 M DIA in THF (8.28 mL, 58.1 mmol) and THF (50 mL). The reaction was cooled to -78°C and 1.6 M nBuLi (23.23 mL, 58.1 mmol) in hexane was added dropwise. The reaction was stirred at -78°C for 30 minutes. But-3-enoic acid (2.00 g, 23.23 mmol) was added to the reaction and the reaction was stirred at -78°C for 30 minutes. Afterwards, EtI (5.44 g, 34.8 mmol) was added. The reaction was slowly warmed to room temperature and stirred at room temperature overnight. The reaction was then quenched with saturated NH ₄ Cl (3 mL). The pH of the reaction was adjusted to <4 using 1 N HCl. The reaction was then extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over MgSO ₄ , filtered, and concentrated. The residue was purified using the ISCO system (0-60% EtOAc/Hex gradient) to give 2-ethylbut-3-enoic acid (450 mg, 2.37 mmol, 10.2% yield) as a clear liquid.

^1H NMR (400MHz, CDCl ₃ ) δ 5.89 - 5.75 (m, 1H), 5.22 - 5.18 (m, 1H), 5.16 (s, 1H), 2.95 (q, J=7.5 Hz, 1H), 1.83 (dt) , J=13.9, 7.2 Hz, 1H), 1.61 (dt, J=13.6, 7.4 Hz, 1H), 0.95 (t, J=7.4 Hz, 3H).

57B. tert-Butyl ((1S)-1-(4-(4-(2-ethylbut-3-enamido)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but- Preparation of 3-en-1-yl)carbamate

(S)-tert-butyl (1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3 prepared as described in Intermediate 32C to RBF. -en-1-yl)carbamate (1000 mg, 2.91 mmol), EtOAc (20 mL), 2-ethylbut-3-enoic acid (332 mg, 2.91 mmol), and pyridine (0.71 mL, 8.74 mmol) Added. The solution was cooled in brine/ice bath and 50% T3P® (2.60 mL, 4.37 mmol) was added. The reaction was stirred at 0°C for 10 minutes and then at room temperature for 60 minutes. The reaction was diluted with EtOAc (30 mL) and washed with saturated NaHCO ₃ (20 mL), water (30 mL), and brine (30 mL). The organic layer was separated, dried over MgSO ₄ , filtered and concentrated. The residue was purified using the ISCO system (0-100% EtOAc/Hex gradient) to give tert-butyl ((1S)-1-(4-(4-(2-ethylbut-3-) as a diastereomeric mixture. Enamido)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (1.10 g, 2.50 mmol, 86% yield) was obtained as yellow Obtained as a solid. MS(ESI) m/z: 440.0 (M+H) ⁺ .

57C. tert-Butyl N-[(9R,10E,13S)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 Preparation of (18),2(6),4,10,14,16-hexaen-13-yl]carbamate

tert-butyl ((1S)-1-(4-(4-(2-ethylbut-3-enamido)-1-methyl-1H-pyrazol-5-yl)pyridin-2- in a microwave vial. yl)but-3-en-1-yl)carbamate (500 mg, 1.138 mmol) and DCE (12 mL) were added. The reaction was purged with Ar for 1 minute. Second generation Grubbs catalyst (386 mg, 0.455 mmol) was then added to the solution. The reaction was sealed and heated in the microwave at 120°C for 30 minutes. The reaction was concentrated and the residue was purified using the ISCO system (0-10% MeOH/CH ₂ Cl ₂ gradient). Two products were isolated. The fast eluting product is tert-butyl N-[(9R,10E)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (75 mg, 0.182 mmol, 16.0% yield), MS(ESI) m/z: 412.2 (M+H) ⁺ and this was carried over to the next, slow eluting product, the other diastereomer, tert-butyl N-[(9S,10E)-9-ethyl-3-methyl-8-oxo-3,4 ,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (75 mg, 0.182 mmol, 16.0% yield), MS(ESI) m/z: 412.2 (M+H) ⁺ .

57D. tert-Butyl N-[(9R,13S)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18 ),2(6),4,14,16-pentaen-13-yl]carbamate production

tert-butyl N-[(9R,10E)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca in three-prong RBF -1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (115 mg, 0.279 mmol), EtOH (10 mL) and PtO ₂ (31.7 mg, 0.140 mmol) was added. The reaction was stirred under H ₂ atmosphere (balloon pressure) for 1 hour. The reaction was carefully filtered through Celite® and concentrated. The residue was purified using the ISCO system (0-10% MeOH/CH ₂ Cl ₂ gradient) to obtain tert-butyl N-[(9R,13S)-9-ethyl-3-methyl-8-oxo-3, 4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (75 mg , 0.181 mmol, 64.9% yield) was obtained as a light brown solid. MS(ESI) m/z: 414.2 (M+H) ⁺ .

57E. (9R,13S)-13-Amino-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) , Preparation of 4,14,16-pentaen-8-one

RBF tert-butyl N-[(9R,13S)-9-ethyl-3-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18),2(6),4,14,16-pentaen-13-yl]carbamate (75 mg, 0.181 mmol), dioxane (3 mL), 4 N HCl (18.14 mmol) and MeOH ( 0.5 mL) was added. The reaction was stirred at room temperature for 5 minutes. The reaction was concentrated, and the residue was purified using reverse-phase preparative HPLC to give (9R,13S)-13-amino-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3. 1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one, trihydrochloride was obtained. The product was dissolved in MeOH (1 mL) to give a clear brown solution. The solution was added to a pre-rinsed Agilent® Stratosphere SPE PL-HCO ₃ MP resin cartridge. Gravity filtration eluting with MeOH gave a clear, slightly brown filtrate. Concentrate (9R,13S)-13-amino-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2( 6),4,14,16-pentaen-8-one (75 mg, 0.177 mmol, 98% yield) was obtained as a beige solid. MS(ESI) m/z: 314.2 (M+H) ⁺ .

57F. (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6), Preparation of 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,14,16-pentaen-8-one trifluoroacetate (5 mg, 6.82 μmol, 26.3% yield) was prepared as described in Intermediate 9 in a manner similar to the procedure described in Example 56. -Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (8 mg, 0.026 mmol), and (9R)-13-amino- 9-ethyl-3-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene- Prepared using 8-one (8 mg, 0.026 mmol).

¹ H NMR (400MHz, CD ₃ OD) δ 8.87 (s, 1H), 8.72 (d, J=5.1 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.64 (dd, J=8.5, 2.3 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.46 (s, 1H), 7.36 (dd, J=5.1, 1.5 Hz, 1H), 6.37 (s, 1H), 6.06 (dd, J=12.5, 4.6 Hz, 1H), 4.03 (s, 3H), 2.46 - 2.36 (m, 1H), 2.26 - 2.12 (m, 1H), 2.03 - 1.92 (m, 2H), 1.69 - 1.56 (m, 2H), 1.45 (d, J=4.8 Hz, 1H), 1.32 - 1.20 (m, 1H), 0.86 (t, J=7.4 Hz, 3H), 0.69 - 0.57 (m, 1H); MS(ESI) m/z: 604.2 (M+H) ⁺ . Analytical HPLC (Method A): RT = 7.23 min, purity = 97.0%; Factor XIa Ki = 0.36 nM, plasma kallikrein Ki = 37 nM.

Example 58

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of 2(6),4,14,16-pentaen-8-one trifluoroacetate

58A. Preparation of 2-isopropylbut-3-enoic acid

To the flame-dried RBF was added 2 M DIA in THF (3.64 ml, 25.6 mmol) and THF (58.1 ml). The reaction was cooled to -78°C and 1.6 M nBuLi in hexanes (15.97 ml, 25.6 mmol) was added. The reaction was stirred at -78°C for 30 minutes. But-3-enoic acid (0.990 ml, 11.62 mmol) was added and the reaction was stirred for an additional 30 minutes. Then, at -78°C, iPrI (1.74 ml, 17.42 mmol) was added and the reaction was slowly warmed to room temperature over 2 hours and then stirred at room temperature overnight. The reaction was quenched with saturated NH ₄ Cl (15 ml). The pH of the solution was adjusted to <4 using 1 N HCl. The reaction was extracted with EtOAc (3 x 30 mL). The combined EtOAc layers were washed with brine (40 mL), dried over MgSO ₄ , filtered and concentrated. The residue was purified using the ISCO system (0-50% EtOAc/Hex gradient) to give 2-isopropylbut-3-enoic acid (800 mg, 6.24 mmol, 53.7% yield) as a clear liquid.

¹ H NMR (400MHz, CDCl ₃ ) δ 5.98 - 5.65 (m, 1H), 5.33 - 5.05 (m, 2H), 2.73 (t, J=8.8 Hz, 1H), 2.08 - 1.95 (m, 1H), 1.09 - 0.74 (m, 6H).

58B. tert-butyl ((1S-[1-(4-{1-methyl-4-[2-(propan-2-yl)but-3-enamido]-1H-pyrazol-5-yl}pyridin- 2-day) Preparation of but-3-en-1-yl]carbamate

(S)-tert-butyl (1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3 prepared as described in Intermediate 32C to RBF. -en-1-yl)carbamate (765 mg, 2.228 mmol), EtOAc (20 mL), 2-isopropylbut-3-enoic acid (286 mg, 2.228 mmol), and pyridine (0.540 mL, 6.68 mmol) was added. The solution was cooled in brine/ice bath and 50% T3P® (1.989 mL, 3.34 mmol) was added. The reaction was stirred at 0°C for 10 minutes and then at room temperature for 60 minutes. The reaction was diluted with EtOAc (30 mL) and washed with saturated NaHCO ₃ (20 mL), water (30 mL), and brine (30 mL). The organic layer was separated, dried over MgSO ₄ , filtered and concentrated. The residue was purified using the ISCO system (0-100% EtOAc/Hex gradient) to give tert-butyl ((1S)-1-(4-(4-(2-isopropylbut-3) as a diastereomeric mixture. -Enamido)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (850 mg, 1.874 mmol, 84% yield) Obtained as a yellow solid. MS(ESI) m/z: 454.2 (M+H) ⁺

58C1 and 58C2. tert-Butyl N-[(9S,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate, and tert-butyl N-[(9R,10E,13S)-3 -methyl-8-oxo-9-(propan-2-yl)-3,4,7,15 tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 ,10,14,16-hexaen-13-yl]Manufacture of carbamate

tert-Butyl ((1S)-1-(4-(4-(2-isopropylbut-3-enamido)-1-methyl-1H-pyrazol-5-yl)pyridin-2 in a microwave vial. -yl)but-3-en-1-yl)carbamate (250 mg, 0.551 mmol) and DCE (15 mL) were added. The reaction was purged with Ar for 1 minute. Second generation Grubbs catalyst (187 mg, 0.220 mmol) was then added. The reaction was sealed and heated in the microwave at 120°C for 60 minutes. The reaction was then concentrated and the residue was purified using reverse phase preparative HPLC to give 58C1, tert-butyl N-[(9S,10E,13S)-3-methyl-8-oxo-, which has a shorter retention time. 9-(Propan-2-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16 -hexaen-13-yl]carbamate trifluoroacetate (50 mg, 0.093 mmol, 16.8% yield), (ESI) m/z: 426.2 (M+H) ⁺ and 58C2 with longer retention time, tert-Butyl N-[(9R,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate trifluoroacetate (50 mg, 0.093 mmol, 16.8% yield), MS (ESI) m/z: 426.2 (M+H) ⁺ was obtained.

58D. tert-Butyl N-[(9R,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] Preparation of octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

tert-butyl N-[(9S,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate trifluoroacetate (20 mg, 0.037 mmol), EtOH (3 mL) and PtO ₂ (4.21 mg, 0.019 mmol) were added. The reaction was stirred under H ₂ atmosphere (balloon pressure) for 1 hour. The reaction was carefully filtered through Celite® and the filtrate was concentrated to give tert-butyl N-[(9R,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4. ,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (12 mg, 0.028 mmol, 76% yield) was obtained. MS(ESI) m/z: 428.2 (M+H) ⁺ .

58E. (9R,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18 ), 2(6),4,14,16-pentaen-8-one production

In a round RBF flask, tert-butyl N-[(9R,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (20 mg, 0.047 mmol), dioxane (3 mL), dioxane 4 N HCl (0.14 mL, 4.68 mmol) and MeOH (0.5 mL) were added. The reaction was stirred at room temperature for 5 minutes. The reaction was concentrated, and the residue was purified using reverse-phase preparative HPLC to obtain (9R,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetra. Azatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-8-one hydrochloride was obtained. The product was added to a pre-rinsed Agilent® Stratosphere SPE PL-HCO ₃ MP resin cartridge. Gravity filtration eluting with MeOH gave a clear, slightly brown filtrate. Concentrate to give (9R,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18),2(6),4,14,16-pentaen-8-one (7 mg, 0.016 mmol, 34.3% yield) was obtained as a solid. MS(ESI) m/z: 328.2 (M+H) ⁺ .

58F. (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of 2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18) , 2(6),4,14,16-pentaen-8-one trifluoroacetate (6 mg, 8.03 μmol, 40.4% yield) was purified as described in Intermediate 9 in a manner similar to the procedure described in Example 56. Prepared 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (6.12 mg, 0.020 mmol), and (9R ,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18), It was prepared using 2(6),4,14,16-pentaen-8-one (6.5 mg, 0.020 mmol).

¹ H NMR (400MHz, CD ₃ OD) δ 8.75 (s, 1H), 8.69 (d, J=5.1 Hz, 1H), 8.07 - 8.01 (m, 1H), 7.82 - 7.78 (m, 1H), 7.71 - 7.66 (m, 1H), 7.65 (s, 1H),

7.60 - 7.57 (m, 1H), 7.52 - 7.47 (m, 1H), 7.36 (dd, J=5.1, 1.5 Hz, 1H), 6.41 (d, J=0.7 Hz, 1H), 6.09 (dd, J= 12.4, 4.3 Hz, 1H), 4.04 (s, 3H), 2.16 (tt, J=12.6, 4.2 Hz, 1H), 2.06 - 1.71 (m, 5H), 1.60 - 1.48 (m, 1H), 1.03 (dd) , J=6.4, 3.7 Hz, 6H), 0.82 (q, J=11.4 Hz, 1H); MS(ESI) m/z: 618.2 (M+H) ⁺ . Analytical HPLC (Method A): RT = 11.50 min, purity = 98.0%; Factor XIa Ki = 56 nM, plasma kallikrein Ki = 3,300 nM.

Example 59

(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18) ,2(6),4,14,16-pentaen-8-one trifluoroacetate

59A. tert-Butyl N-[(9S,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] Preparation of octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

tert-butyl N-[(9R,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7 prepared as described in Example 58C2 in 3-neck RBF ,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate trifluoroacetate (15 mg, 0.028 mmol), EtOH (3 mL) and PtO ₂ (3.16 mg, 0.014 mmol) were added. The reaction was stirred under H ₂ atmosphere (balloon pressure) for 1 hour. The reaction was carefully filtered through Celite® and the filtrate was concentrated to give tert-butyl N-[(9S,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4. ,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (10 mg, 0.023 mmol, 84% yield) was obtained as a brown solid. MS(ESI) m/z: 618.2 (M+H) ⁺ .

59B. (9S,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18 ), 2(6),4,14,16-pentaen-8-one production

To RBF, tert-butyl N-[(9S,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (20 mg, 0.047 mmol), dioxane (3 mL), 4 in dioxane N HCl (0.142 mL, 4.68 mmol) and MeOH (0.5 mL) were added. The reaction was stirred at room temperature for 5 minutes. The reaction was concentrated, and the residue was purified using reverse phase preparative HPLC to obtain (9S,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetra. Azatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one hydrochloride was obtained. The product was added to a pre-rinsed Agilent® Stratosphere SPE PL-HCO ₃ MP resin cartridge. Gravity filtration eluting with MeOH gave a clear, slightly brown filtrate. Concentrate to obtain (9S,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18),2(6),4,14,16-pentaen-8-one (1.5 mg, 3.43 μmol, 7.34% yield) was obtained as a beige solid. MS(ESI) m/z: 328.2 (M+H) ⁺ .

59C. (9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of 2(6),4,14,16-pentaen-8-one trifluoroacetate

(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18) ,2(6),4,14,16-pentaen-8-one trifluoroacetate (0.6 mg, 0.778 μmol, 21.23% yield) was purified as described in Intermediate 9 in a manner similar to the procedure described in Example 56. Prepared 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (1.129 mg, 3.66 μmol), and (9S ,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18), Prepared using 2(6),4,14,16-pentaen-8-one (1.2 mg, 3.66 μmol).

¹ H NMR (400MHz, CD ₃ OD) δ 8.80 (s, 1H), 8.76 (d, J=5.1 Hz, 1H), 8.38 - 8.36 (m, 1H), 7.92 (d, J=2.2 Hz, 1H) , 7.79 - 7.75 (m, 1H), 7.73 (s, 1H), 7.70 - 7.65 (m, 1H), 7.55 (dd, J=5.1, 1.5 Hz, 1H), 7.52 (s, 1H), 6.40 (s , 1H), 5.98 (d, J=9.2 Hz, 1H), 4.08 (s, 3H), 2.46 - 2.27 (m, 2H), 2.17 - 2.01 (m, 3H), 1.87 - 1.67 (m, 3H), 1.43 (br. s., 1H), 0.97 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H); MS(ESI) m/z: 618.2 (M+H) ⁺ . Analytical HPLC (Method A): RT = 11.52 min, purity = 95.0%; Factor XIa Ki = 3.5 nM, plasma kallikrein Ki = 370 nM.

Example 60

(9S,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca -Preparation of 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9S,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (0.8 mg, 1.013 μmol, 3.32% yield) was purified as an intermediate in a manner similar to the procedure described in Example 56. 6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl) pyrimidin-4-ol ( 12.43 mg, 0.031 mmol) and (9S,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] Prepared using octadeca-1(18),2(6),4,14,16-pentaen-8-one (10 mg, 0.031 mmol).

¹ H NMR (400MHz, CD ₃ OD) δ 8.80 (s, 1H), 8.75 (d, J=5.1 Hz, 1H), 8.27 (s, 1H), 7.87 - 7.83 (m, 1H), 7.69 (s, 1H), 7.56 - 7.49 (m, 2H), 7.48 (s, 1H), 6.61 (s, 1H), 6.01 (d, J=8.8 Hz, 1H), 4.06 (s, 3H), 2.33 - 2.24 (m , 1H), 2.13 - 1.99 (m, 3H), 2.14 - 1.97 (m, 4H), 1.83 - 1.69 (m, 2H), 1.42 (br. s., 1H), 1.33 - 1.23 (m, 1H), 0.94 (d, J=6.8 Hz, 3H), 0.89 (d, J=6.4 Hz, 3H); MS(ESI) m/z: 636.2 (M+H) ⁺ . Analytical HPLC (Method A): RT = 11.266 min, purity = 95.0%; Factor XIa Ki = 0.53 nM, plasma kallikrein Ki = 40 nM.

Example 61

(9R,13S)-13-{4-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- Preparation of ontrifluoroacetate

61A. Preparation of 2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To dry RBF was added 1-chloro-4-(difluoromethyl)-2-fluorobenzene (180 mg, 0.997 mmol) and THF (3 mL). The reaction was cooled to -78°C and 2 M LDA (0.498 mL, 0.997 mmol) in THF was added dropwise. The reactant immediately turned dark red after addition. The reaction was stirred at -78°C for 5 minutes, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (371 mg, 1.994 mmol) was added in one portion. Added. The reaction was stirred at -78°C for 20 minutes. The color changed to light yellow. The reaction was partitioned between EtOAc (30 mL) and water (20 mL). The organic layer was separated, washed with water (20 mL) and brine (20 mL), dried over MgSO ₄ , filtered and concentrated. The residue was purified using the ISCO system (0-30% EtOAc/Hex gradient) to give 2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5, 5-Tetramethyl-1,3,2-dioxaborolane (125 mg, 0.408 mmol, 40.9% yield) was obtained as a light brown oil.

^1H NMR (400MHz, CDCl ₃ ) δ 7.45 (t, J=7.8 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.10 - 6.74 (m, 1H), 1.31 (s, 12H).

61B. Preparation of 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-methoxypyrimidine

2-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (120) in a microwave vial. mg, 0.391 mmol), 4-chloro-6-methoxypyrimidine (56.6 mg, 0.391 mmol), toluene (2 mL), EtOH (1 mL) and 2 M Na ₂ CO ₃ (0.587 mL, 1.174 mmol). Added. The reaction was purged with Ar, and Pd(PPh ₃ ) ₄ (45 mg, 0.039 mmol) was added. The reaction was sealed and stirred in the microwave at 120°C for 1 hour. The reaction was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, washed with water (10 mL) and brine (15 mL), dried over MgSO ₄ , filtered and concentrated. The residue was purified using the ISCO system (0-30% EtOAc/Hex gradient) to give 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-methoxypyrimidine. (40 mg, 0.139 mmol, 35.4% yield) was obtained as a white solid.

^1H NMR (400MHz, CDCl ₃ ) δ 8.88 (d, J=0.9 Hz, 1H), 7.64 - 7.57 (m, 1H), 7.56 - 7.50 (m, 1H), 7.11 - 6.76 (m, 2H), 4.06 (s, 3H).

61C. Preparation of 6-(3-chloro-6-(difluoromethyl)-2 fluorophenyl)pyrimidin-4-ol

RBF was incubated with 4-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)-6-methoxypyrimidine (40 mg, 0.139 mmol), AcOH (0.5 mL) and 48% HBr (0.784 mL, 6.93 mmol) was added. The reaction was stirred at 85°C for 45 minutes. Toluene (25 mL) was then added and the reaction was concentrated. The residue was then partitioned between EtOAc (25 mL) and saturated aqueous NaHCO ₃ (25 mL). The organic layer was separated, washed with water (15 mL) and brine (15 mL), dried over MgSO ₄ , filtered and concentrated. The residue was purified using the ISCO system (0-100% EtOAc/Hex gradient) to give 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyrimidin-4-ol ( 36 mg, 0.131 mmol, 95% yield) was obtained as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 13.25 (br. s., 1H), 8.28 (s, 1H), 7.70 - 7.57 (m, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.16 - 6.79 (m, 1H), 6.72 (br. s., 1H).

61D. (9R,13S)-13-{4-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaene-8- Preparation of ontrifluoroacetate

(9R,13S)-13-{4-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- Monotrifluoroacetate (3.1 mg, 4.44 μmol, 7.38% yield) was reacted with 6-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)pyri in a manner similar to the procedure described in Example 56. Prepared using midin-4-ol (16.51 mg, 0.060 mmol).

¹ H NMR (400MHz, CD ₃ OD) δ 8.78 (d, J=5.3 Hz, 1H), 7.80 - 7.74 (m, 2H), 7.60 (d, J=8.6 Hz, 1H), 7.56 (dd, J= 5.3, 1.5 Hz, 1H), 7.53 (s, 1H), 7.16 - 6.84 (m, 1H), 6.67 (s, 1H), 6.08 (dd, J=12.8, 4.2 Hz, 1H), 4.08 (s, 3H) ), 2.75 (td, J=6.8, 3.2 Hz, 1H), 2.40 (tt, J=12.7, 4.6 Hz, 1H), 2.19 - 2.05 (m, 2H), 1.71 - 1.60 (m, 1H), 1.53 ( ddd, J=15.0, 9.9, 5.5 Hz, 1H), 1.05 (d, J=7.0 Hz, 3H), 0.76 (br. s., 1H); MS(ESI) m/z: 557.1 (M+H) ⁺ . Analytical HPLC (Method A): RT = 7.516 min, purity = 96.0%; Factor XIa Ki = 2.5 nM, plasma kallikrein Ki = 45 nM.

Example 62

(9R,13S)-13-{4-[3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4,14,16-penta Preparation of en-8-one trifluoroacetate

62A. Preparation of 1-chloro-4-(1,1-difluoroethyl)-2-fluorobenzene

1-(4-Chloro-3-fluorophenyl)ethanone (1 g, 5.79 mmol), CH ₂ Cl ₂ (10 mL) and DAST (2.297 mL, 17.38 mmol) were added to the sealed tube. The reaction was sealed and stirred at 45°C for 8 hours. The reaction was carefully quenched with cold saturated NaHCO ₃ over 30 minutes until the pH was above 7. The organic layer was separated, washed with water, dried over MgSO ₄ , filtered and concentrated. The residue was purified using the ISCO system (0-10% EtOAC/Hex gradient) to obtain 1-chloro-4-(1,1-difluoroethyl)-2-fluorobenzene (300 mg, 1.54 mmol, 26.6% yield) was obtained as a light brown liquid.

^1H NMR (400MHz, CDCl ₃ ) δ 7.49 - 7.42 (m, 1H), 7.32 - 7.27 (m, 1H), 7.25 - 7.20 (m, 1H), 1.90 (t, J=18.2 Hz, 3H).

62B. Preparation of 2-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To dry RBF was added 1-chloro-4-(1,1-difluoroethyl)-2-fluorobenzene (230 mg, 1.182 mmol) and THF (3 mL). The reaction was cooled to -78°C and 2 M LDA solution (0.71 mL, 1.418 mmol) was added dropwise. The reaction turned red after addition. The reaction was stirred at -78°C for 5 minutes, then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (440 mg, 2.364 mmol) was added once. was added to. The reaction was stirred at -78°C for an additional 20 minutes. The color changed to light yellow. The reaction was partitioned between EtOAc (30 mL) and water (20 mL). The organic layer was separated, washed with water (20 mL) and brine (20 mL), dried over MgSO ₄ , filtered and concentrated. The residue was purified using the ISCO system (0-30% EtOAc/Hex gradient) to obtain 2-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)-4, 4,5,5-Tetramethyl-1,3,2-dioxaborolane (330 mg, 1.030 mmol, 87% yield) was obtained as a clear oil.

^1H NMR (400MHz, CDCl ₃ ) δ 7.43 (t, J=7.9 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 1.93 (t, J=18.3 Hz, 3H), 1.38 (s, 12H).

62C. Preparation of 4-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)-6-methoxypyrimidine

2-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa in a microwave vial. Borolane (325 mg, 1.014 mmol), 4-chloro-6-methoxypyrimidine (147 mg, 1.014 mmol), toluene (4 mL), EtOH (2 mL) and 2 M Na ₂ CO ₃ (1.52 mL, 3.04 mmol) was added. The reaction was purged with Ar, and Pd(PPh ₃ ) ₄ (116.7 mg, 0.101 mmol) was added. The reaction was sealed and stirred in the microwave at 120°C for 1 hour. The reaction was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, washed with water (10 mL) and brine (15 mL), dried over MgSO ₄ , filtered and concentrated. The residue was purified using the ISCO system (0-30% EtOAc/Hex gradient) to give 4-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)-6- Methoxypyrimidine (40 mg, 0.132 mmol, 13.03% yield) was obtained as a white solid.

^1H NMR (400MHz, CDCl ₃ ) δ 8.84 (d, J=1.1 Hz, 1H), 7.52 (d, J=7.3 Hz, 1H), 7.36 (dd, J=8.6, 1.3 Hz, 1H), 6.81 ( s, 1H), 4.05 (s, 3H), 1.91 (t, J=18.6 Hz, 3H); MS(ESI) m/z: 303.0, 305.0 (M+H) ⁺ .

62D. Preparation of 6-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)pyrimidin-4-ol

To RBF, 4-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)-6-methoxypyrimidine (35 mg, 0.116 mmol), AcOH (0.5 mL) and HBr (0.654 mL, 5.78 mmol) was added. The reaction was stirred at 85°C for 45 minutes. Toluene (25 mL) was then added and the reaction was concentrated. The residue was partitioned between EtOAc (25 mL) and saturated NaHCO ₃ (25 mL). The organic layer was separated, washed with water (15 mL) and brine (15 mL), dried over MgSO ₄ , filtered and concentrated. The residue was purified using the ISCO system (0-100% EtOAc/Hex gradient) to give 6-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)pyrimidine- 4-ol (28 mg, 0.097 mmol, 84% yield) was obtained as a white solid. MS(ESI) m/z: 289, 291.0 (M+H) ⁺ .

62E. (9R,13S)-13-{4-[3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-penta Preparation of en-8-one trifluoroacetate

(9R,13S)-13-{4-[3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4,14,16-penta En-8-one trifluoroacetate (30 mg, 0.042 mmol, 69.9% yield) was purified from 6-{5-chloro-2-[4-(trifluoromethyl)- in a manner similar to the procedure described in Example 56. 1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol to 6-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl) Prepared by replacing with pyrimidin-4-ol (22.2 mg, 0.06 mmol). ¹ H NMR (400MHz, CD ₃ OD) δ 8.99 (br. s., 1H), 8.74 (d, J=4.2 Hz, 1H), 7.78 (s, 1H), 7.65 (t, J=7.8 Hz, 1H) ), 7.58 (d, J=3.7 Hz, 1H), 7.50 - 7.39 (m, 2H), 6.53 (s, 1H), 6.01 (d, J=9.9 Hz, 1H), 4.02 (s, 3H), 2.67 (br. s., 1H), 2.43 - 2.31 (m, 1H), 2.06 (br. s., 2H), 1.89 (t, J=18.6 Hz, 3H), 1.66 - 1.53 (m, 1H), 1.45 (br. s., 1H), 0.98 (d, J=6.8 Hz, 3H), 0.73 (br. s., 1H); MS(ESI) m/z: 636.2 (M+H) ⁺ . Analytical HPLC (Method A): RT = 11.078 min, purity = 96.0%; Factor XIa Ki = 16 nM, plasma kallikrein Ki = 240 nM.

Example 63

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), Preparation of 4,14,16-pentaen-8-one

6-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol (0.018 g, prepared as described in Intermediate 7, To 0.060 mmol), a solution of HATU (0.030 g, 0.078 mmol) and DBU (0.014 mL, 0.090 mmol) in CH ₃ CN (0.5 ml) was added. After 30 min, (9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 , prepared as described in Intermediate 29. ]Octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.019 g, 0.060 mmol) was added. After 18 hours, the reaction was diluted with DMF, filtered and concentrated. The residue was purified by reverse phase HPLC using Phenomenex® Luna 5U 30 x100 mm (90:10 AcN/H ₂ O in 10:90 ACN/H ₂ O, 0.1%TFA) (10 min gradient starting at 20% B). It was purified. The desired fraction was concentrated and lyophilized to (9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl] -6-oxo-1,6-dihydropyrimidin-1-yl}-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one (4.5 mg, 12%) was obtained as a white solid. MS(ESI) m/z: 591.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.25 (s, 1H), 8.20 (d, J=1.1 Hz, 1H), 7.91 - 7.84 (m, 1H), 7.84 - 7.77 (m, 2H), 7.60 - 7.49 (m, 3H), 7.38 (d, J=8.6 Hz, 1H), 7.12 (d, J=9.5 Hz, 1H), 6.59 (s, 1H), 5.79 (dd, J=12.9, 3.2 Hz, 1H) ), 4.08 - 4.00 (m, 3H), 2.52 (td, J=6.8, 3.4 Hz, 1H), 2.41 - 2.29 (m, 1H), 2.15 - 2.04 (m, 1H), 1.90 (d, J=4.8 Hz, 1H), 1.65 - 1.45 (m, 2H), 1.29 - 1.19 (m, 1H), 1.14 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT = 7.41 min, purity = 95%; Factor XIa Ki = 0.25 nM, plasma kallikrein Ki = 34 nM.

Example 64

(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-16-fluoro-3 Preparation of ,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a solution of 6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol hydrobromide (0.017 g, 0.053 mmol) prepared as described in Intermediate 4 in CH ₃ CN (1 ml) , HATU (0.026 g, 0.068 mmol) and DBU (0.028 mL, 0.184 mmol) were added. After 1 hour, (9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 , prepared as described in Intermediate 29. ]Octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.019 g, 0.053 mmol) was added. After 18 hours, the reaction was diluted with DMF, filtered and concentrated. The residue was purified by reverse phase HPLC followed by preparative LCMS to give (9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydro. Pyrimidin-1-yl]-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,14,16-pentaen-8-one (3.4 mg, 11.9%) was obtained. MS(ESI) m/z: 542.1 (M+H) ⁺ .

^1H NMR ((500MHz, DMSO-d ₆ ) δ 9.23 (s, 1H), 8.69 (br. s., 1H), 7.84 - 7.73 (m, 1H), 7.61 - 7.50 (m, 2H), 7.45 ( s, 1H), 7.38 - 7.32 (m, 1H), 7.29 - 7.19 (m, 1H), 6.74 (s, 1H), 5.66 (d, J=12.5 Hz, 1H), 3.98 (s, 3H), 2.42 (br. s., 1H), 2.10 - 1.97 (m, 1H), 1.88 (br. s., 1H), 1.45 (d, J=7.3 Hz, 1H), 1.21 (br. s., 1H), 1.11 (br. s., 1H), 0.97 (d, J=6.4 Hz, 3H). Analytical HPLC (Method C) RT = 1.50 min, purity = 99%, factor XIa Ki = 26 nM, plasma kallikrein Ki = 450 nM.

Example 65

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4,14 , Preparation of 16-pentaen-8-one

6-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol (13.07 mg, prepared as described in Intermediate 7, To 0.045 mmol), a solution of HATU (22.14 mg, 0.058 mmol) and DBU (0.017 mL, 0.112 mmol) in ACN (0.5 ml) was added. After 30 min, (9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 prepared as described in Intermediate 31. (18),2(6),4,14,16-pentaen-8-one, hydrochloride (15 mg, 0.045 mmol) was added, and the reaction was stirred for 18 hours. The reaction was then diluted with DMF, filtered and concentrated. The residue was purified by reverse phase HPLC followed by preparative LCMS to give (9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazole-1) -yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one (3.2 mg, 12%) was obtained. MS(ESI) m/z: 573.3 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.15 (s, 1H), 8.43 - 8.32 (m, 2H), 8.00 - 7.93 (m, 2H), 7.84 (s, 1H), 7.68 - 7.59 (m, 2H), 7.59 - 7.50 (m, 2H), 7.41 (s, 1H), 7.28 - 6.99 (m, 2H), 6.56 (s, 1H), 5.60 (d, J=11.3 Hz, 1H), 4.03 - 3.90 (m, 3H), 2.32 (br. s., 1H), 1.94 - 1.79 (m, 2H), 1.41 (d, J=5.2 Hz, 1H), 1.14 (br. s., 2H), 0.96 (d , J=6.4 Hz, 3H). Analytical HPLC (Method C) RT=1.41 min, purity=98%; Factor XIa Ki = 0.23 nM, plasma kallikrein Ki = 22 nM.

Example 66

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14, Preparation of 16-pentaen-8-one

6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidine- prepared as described in Intermediate 9 in CH ₃ CN (0.5 ml) HATU (0.041 g, 0.109 mmol) and DBU (0.019 mL, 0.126 mmol) were added to a 1-dram vial containing a white suspension of 4-ol (0.026 g, 0.084 mmol). After 30 minutes, (9R,13S)-13-amino- prepared as described in Intermediate 31 was free-based via a basic cartridge in DCM/MeOH and dried in CH ₃ CN/DMF (0.5 ml). 3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one ( 0.025 g, 0.084 mmol) was added. After 18 hours, the reaction was diluted with DMF, filtered and purified by reverse phase HPLC with Phenomenex® Luna 5U 30 x 100 mm (10:90 MeOH/H ₂ O to 90:10 MeOH/H ₂ O, 0.1% TFA). Purified using (20% B starting 10 min gradient) to (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazole-1- I) phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ] octadeca- 1(18),2(6),4,14,16-pentaen-8-one (13.9 mg, 28% yield) was obtained as a white solid. MS(ESI) m/z: 589.2 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.37 - 8.33 (m, 1H), 8.19 (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.80 - 7.72 (m, 2H), 7.67 - 7.55 (m, 3H), 7.52 (s, 1H), 7.34 (d, J=7.3 Hz, 1H), 6.43 (d, J=0.7 Hz, 1H), 5.84 (dd, J=13.1, 3.2 Hz, 1H) ), 4.04 (s, 3H), 2.55 - 2.46 (m, 1H), 2.41 - 2.30 (m, 1H), 2.17 - 2.05 (m, 1H), 1.92 - 1.84 (m, 1H), 1.66 - 1.53 (m , 2H), 1.22 (br. s., 1H), 1.16 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT = 8.25 min, purity = 95%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 8 nM.

Example 67

(9R)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydro Pyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16 -Preparation of pentaen-8-one

Example 65 was also purified by reverse phase HPLC followed by preparative LCMS to give (9R)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazole-1 -yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one was obtained as the first eluting diastereomer (1.4 mg, 5.4%). MS(ESI) m/z: 573.3 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.08 (s, 1H), 8.71 (s, 1H), 8.39 (s, 1H), 8.04 - 7.94 (m, 1H), 7.86 (s, 1H), 7.70 - 7.58 (m, 2H), 7.58 - 7.48 (m, 2H), 7.42 (s, 1H), 7.25 - 7.03 (m, 2H), 6.61 (s, 1H) , 5.60 (d, J=13.1 Hz, 1H), 3.98 (s, 2H), 2.41 - 2.30 (m, 2H), 1.82 (br. s., 1H), 1.68 (d, J=10.1 Hz, 1H) , 1.37 (d, J=11.0 Hz, 1H), 1.11 (br. s., 2H), 1.07 (d, J=6.4 Hz, 3H). Analytical HPLC (Method C) RT=1.39 min, purity=100%; Factor XIa Ki = 5 nM, plasma kallikrein Ki = 256 nM.

Example 68

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo [ _12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one

6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidine- prepared as described in Intermediate 9 in CH ₃ CN (0.8 ml) To a solution of 4-ol (0.031 g, 0.100 mmol) was added HATU (0.049 g, 0.129 mmol) and DBU (0.023 mL, 0.149 mmol). After 30 min, (9R,13S)-13-amino-3-( ^2H ₃ )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ² prepared as described in Intermediate 36. ^,6 ] octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.03 g, 0.100 mmol) was added (rinsed with 0.2 ml DMF). After 18 hours, the reaction was diluted with DMF, filtered and concentrated. The residue was purified by reverse phase HPLC using Phenomenex® Luna 5U 30x100 mm (90:10 MeOH/H ₂ O in 10:90 MeOH/H ₂ O, 0.1% TFA) (25% B starting, 14 min gradient). Purified. The desired fraction was concentrated and lyophilized to (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]- 6-oxo-1,6-dihydropyrimidin _- 1-yl}-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,14,16-pentaen-8-one (19.6 mg, 33% yield) was obtained as a tan solid. MS(ESI) m/z: 592.4 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.33 (s, 1H), 8.18 (s, 1H), 7.87 (d, J=2.2 Hz, 1H), 7.80 - 7.71 (m, 2H), 7.68 - 7.55 ( m, 3H), 7.54 - 7.50 (m, 1H), 7.33 (d, J=7.5 Hz, 1H), 6.42 (s, 1H), 5.83 (dd, J=12.8, 3.1 Hz, 1H), 2.56 - 2.45 (m, 1H), 2.38 - 2.29 (m, 1H), 2.18 - 2.06 (m, 1H), 1.94 - 1.82 (m, 1H), 1.67 - 1.52 (m, 2H), 1.22 (br. s., 1H) ), 1.15 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT = 8.44 min, 95% purity; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 6 nM.

Example 69

(10R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-10-methyl-3,8-diazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5 Preparation of 15,17-hexaen-9-one trifluoroacetate

6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluoro prepared as described in Intermediate 10 in CH ₃ CN (0.2 ml) Phenyl] To a solution of pyrimidin-4-ol (4.42 mg, 0.014 mmol) was added HATU (6.69 mg, 0.018 mmol) and DBU (3.06 μl, 0.020 mmol). After 30 min, (10R,14S)-14-amino-10-methyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1 (19), prepared as described in Intermediate 38; 2(7),3,5,15,17-hexaen-9-one (0.004 g, 0.014 mmol) was added along with DMF (0.2 ml). After 18 hours, the reaction was diluted with DMF, filtered and concentrated. The residue was purified by reverse phase HPLC using Phenomenex® Luna 5U 30x100 mm (10:90 ACN/H ₂ O to 90:10 ACN/H ₂ O, 0.1% TFA) (20% B starting, 14 min gradient). Purified (10R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6- oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3 ,5,15,17-hexaen-9-one trifluoroacetate (2 mg, 20% yield) was obtained as a white solid. MS(ESI) m/z: 604.4 (M+H) ⁺ .

^1H NMR (400MHz, CD ₃ OD) δ 8.69 - 8.65 (m, 1H), 8.38 - 8.30 (m, 2H), 8.00 - 7.91 (m, 2H), 7.91 - 7.84 (m, 1H), 7.74 (d) , J=7.9 Hz, 1H), 7.69 - 7.63 (m, 2H), 7.55 (dd, J=8.6, 1.5 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 6.64 (s, 1H) , 5.83 (dd, J=12.9, 3.4 Hz, 1H), 2.55 (t, J=6.7 Hz, 1H), 2.40 - 2.29 (m, 1H), 2.21 - 2.10 (m, 1H), 1.89 (br. s) ., 1H), 1.65 - 1.51 (m, 2H), 1.33 (d, J=9.7 Hz, 1H), 1.15 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT = 6.32 min. purity = 100%; Factor XIa Ki = 1.1 nM, plasma kallikrein Ki = 54 nM.

Example 70

1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3 -Fluorophenyl)-1H-1,2,3-triazole-4-carbonitrile production

1-[4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2 prepared as described in Intermediate 12 in CH ₃ CN (0.4 ml) To a solution of ,3-triazole-4-carbonitrile (13.0 mg, 0.041 mmol) was added HATU (0.020 g, 0.053 mmol) and DBU (9.28 μl, 0.062 mmol). After 0.5 h, (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ² prepared as described in Intermediate 35. ^,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (14.0 mg, 0.041 mmol) was added along with DMF (0.2 ml). Additional CH ₃ CN (0.2 ml) and DMF (0.2 ml) were added to rinse the vial and dissolve the reagent. After 18 hours, the reaction was diluted with DMF, filtered and concentrated. The residue was purified by reverse phase HPLC using Phenomenex® Luna 5U 30x100 mm (10:90 ACN/H ₂ O to 90:10 ACN/H ₂ O, 0.1% TFA) (20% B starting, 14 min gradient). Purified to 1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo [12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl} -3-Fluorophenyl)-1H-1,2,3-triazole-4-carbonitrile (6 mg, 24.7% yield) was obtained as a white solid. MS(ESI) m/z: 643.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.96 (br. s., 1H), 8.22 (br. s., 1H), 7.90 (d, J=6.8 Hz, 1H), 7.79 (br. s., 2H), 7.71 - 7.55 (m, 4H), 7.39 (br. s., 1H), 6.71 (br. s., 1H), 5.84 (d, J=9.9 Hz, 1H), 2.52 (br. s. , 1H), 2.37 (br. s., 1H), 2.19 - 2.01 (m, 1H), 2.01 - 1.87 (m, 1H), 1.59 (br. s., 2H), 1.23 (br. s., 1H) ), 1.17 (br. s., 3H). Analytical HPLC (Method A) rt = 8.83 min, purity = 99%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 4 nM.

Example 71

(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( Preparation of 18),2(6),4,14,16-pentaen-8-one

6-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl] prepared as described in Intermediate 16 in CH ₃ CN (0.4 ml) phenyl} To a solution of pyrimidin-4-ol (0.014 g, 0.043 mmol) was added HATU (0.021 g, 0.056 mmol) and DBU (9.78 μl, 0.065 mmol). After 30 min, (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ² prepared as described in Intermediate 35. ^,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.14 g, 0.043 mmol) was added along with DMF (0.2 ml). Additional CH ₃ CN (0.2 ml) and DMF (0.2 ml) were added to rinse the vial and dissolve the reagent. After 18 hours, the reaction was diluted with DMF, filtered and concentrated. The residue was purified by reverse phase HPLC using Phenomenex® Luna 5U 30x100 mm (10:90 ACN/H ₂ O to 90:10 ACN/H ₂ O, 0.1% TFA) (20% B starting, 14 min gradient). Purify (9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6- Oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one (9.9 mg, 35.7%) was obtained as a white solid. MS(ESI) m/z: 641.5 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.53 (t, J=1.3 Hz, 1H), 8.19 (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.82 - 7.72 (m, 3H) , 7.68 (s, 1H), 7.65 - 7.56 (m, 3H), 7.38 (d, J=7.5 Hz, 1H), 7.20 - 6.81 (m, 1H), 6.42 (d, J=0.7 Hz, 1H), 5.82 (dd, J=12.8, 3.3 Hz, 1H), 2.50 (ddd, J=10.2, 6.9, 3.4 Hz, 1H), 2.35 (d, J=12.5 Hz, 1H), 2.19 - 2.08 (m, 1H) , 1.97 - 1.86 (m, 1H), 1.65 - 1.52 (m, 2H), 1.27 - 1.20 (m, 1H), 1.16 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT = 8.79 min, purity = 100%; Factor XIa Ki = 0.17 nM, plasma kallikrein Ki = 46 nM.

Example 72

(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-( ^2H ₃ )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( Preparation of 18),2(6),4,14,16-pentaen-8-one

6-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl] prepared as described in Intermediate 16 in CH ₃ CN (0.4 ml) phenyl} To a solution of pyrimidin-4-ol (0.014 g, 0.043 mmol) was added HATU (0.021 g, 0.056 mmol) and DBU (9.78 μl, 0.065 mmol). After 30 min, (9R,13S)-13-amino-3-( ^2H ₃ )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ² prepared as described in Intermediate 36 ^,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.13 g, 0.043 mmol) was added along with DMF (0.2 ml). Additional CH ₃ CN (0.2 ml) and DMF (0.4 ml) were added to dissolve the reagents. After 18 hours, the reaction was diluted with DMF, filtered and concentrated. The residue was purified by reverse phase HPLC using Phenomenex® Luna 5U 30x100 mm (10:90 ACN/H ₂ O to 90:10 ACN/H ₂ O, 0.1% TFA) (20% B starting, 14 min gradient). Purify (9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6- Oxo-1,6-dihydropyrimidin _- 1-yl)-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one (10.5 mg, 39%) was obtained as a white solid. MS(ESI) m/z: 608.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.52 (t, J=1.3 Hz, 1H), 8.14 (s, 1H), 7.93 - 7.87 (m, 1H), 7.75 (dd, J=8.5, 2.3 Hz, 2H), 7.72 - 7.66 (m, 1H), 7.64 - 7.54 (m, 2H), 7.54 - 7.50 (m, 1H), 7.35 - 7.30 (m, 1H), 7.14 - 6.83 (m, 1H), 6.43 ( d, J=0.7 Hz, 1H), 5.83 (dd, J=13.0, 3.3 Hz, 1H), 2.49 (dt, J=6.9, 3.4 Hz, 1H), 2.40 - 2.27 (m, 1H), 2.09 (d , J=12.3 Hz, 1H), 1.95 - 1.84 (m, 1H), 1.67 - 1.52 (m, 2H), 1.21 (d, J=6.8 Hz, 1H), 1.16 (d, J=6.8 Hz, 3H) Analytical HPLC (Method A) RT = 7.94 min, purity = 99%; Factor XIa Ki = 0.15 nM, plasma kallikrein Ki = 21 nM.

Example 73

1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-( ^2H ₃ )methyl-9-methyl-8-oxo-3,4,7-triazatri Cyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidine-4 Preparation of -1}phenyl)-1H-1,2,3-triazole-4-carbonitrile

1-[4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2 prepared as described in Intermediate 12 in CH ₃ CN (0.4 ml) To a solution of ,3-triazole-4-carbonitrile (0.010 g, 0.032 mmol) was added HATU (0.016 g, 0.041 mmol) and DBU (7.14 μl, 0.047 mmol). After 30 min, (9R,13S)-13-amino-3-( ^2H ₃ )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ² prepared as described in Intermediate 36. ^,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.095 g, 0.032 mmol) was added along with DMF (0.2 ml). Additional CH ₃ CN (0.2 ml) and DMF (0.2 ml) were added to dissolve the reagents. After 18 hours, the reaction was diluted with DMF, filtered and concentrated. The residue was purified by reverse phase HPLC using Phenomenex® Luna 5U 30x100 mm (90:10 ACN/H ₂ O in 10:90 ACN/H ₂ O, 0.1% TFA) (20% B starting, 14 min gradient). Purified to produce 1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-( ^2H ₃ )methyl-9-methyl-8-oxo-3,4,7-tri Azatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidine -4-yl}phenyl)-1H-1,2,3-triazole-4-carbonitrile (4.7 mg, 24%) was obtained as a white solid. MS(ESI) m/z: 601.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.94 (s, 1H), 8.16 (s, 1H), 7.90 (dd, J=8.7, 7.6 Hz, 1H), 7.77 (s, 1H), 7.70 - 7.56 ( m, 3H), 7.56 - 7.49 (m, 1H), 7.32 (d, J=7.7 Hz, 1H), 6.79 - 6.66 (m, 1H), 5.85 (dd, J=12.7, 3.2 Hz, 1H), 2.50 (ddd, J=10.2, 6.7, 3.5 Hz, 1H), 2.39 - 2.30 (m, 1H), 2.20 - 2.06 (m, 1H), 1.90 (dd, J=9.6, 4.5 Hz, 1H), 1.69 - 1.53 (m, 2H), 1.28 - 1.22 (m, 1H), 1.16 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT = 7.99 min, purity = 97%; Factor XIa Ki = 0.15 nM, plasma kallikrein Ki = 9 nM.

Example 74

1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl) -Manufacture of 1H-1,2,3-triazole-4-carbonitrile

1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole prepared as described in Intermediate 18 in CH ₃ CN (0.4 ml) To a solution of -4-carbonitrile (0.016 g, 0.054 mmol) was added HATU (0.026 g, 0.070 mmol) and DBU (0.012 mL, 0.080 mmol). After 30 min, (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ² prepared as described in Intermediate 35. ^,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.018 g, 0.054 mmol) was added along with DMF (0.5 ml). After 18 hours, the reaction was diluted with DMF, filtered and concentrated. The residue was purified by reverse phase HPLC using Phenomenex® Luna 5U 30x100 mm (10:90 ACN/H ₂ O to 90:10 ACN/H ₂ O, 0.1% TFA) (20% B starting, 14 min gradient). Purified to 1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3 .1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl} Phenyl)-1H-1,2,3-triazole-4-carbonitrile (11.7 mg, 34%) was obtained as a white solid. MS(ESI) m/z: 616.2 (M+H) ⁺ .

^1H NMR (400MHz, CD ₃ OD) δ 8.96 (s, 1H), 8.19 (s, 1H), 7.94 - 7.89 (m, 1H), 7.84 - 7.74 (m, 4H), 7.72 - 7.66 (m, 1H) ), 7.66 - 7.61 (m, 1H), 7.60 - 7.55 (m, 1H), 7.40 (d, J=7.5 Hz, 1H), 6.52 (s, 1H), 5.83 (dd, J=12.9, 3.4 Hz, 1H), 2.50 (td, J=6.6, 3.7 Hz, 1H), 2.42 - 2.31 (m, 1H), 2.17 - 2.07 (m, 1H), 1.90 (dd, J=10.0, 4.7 Hz, 1H), 1.63 - 1.53 (m, 2H), 1.28 - 1.20 (m, 1H), 1.16 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT = 8.82, purity = 97%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 10 nM.

Example 75

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( Preparation of 18),2(6),4,14,16-pentaen-8-one

6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl] prepared as described in Intermediate 15 in CH ₃ CN (0.8 ml) phenyl} To a solution of pyrimidin-4-ol (0.029 g, 0.084 mmol) was added HATU (0.041 g, 0.109 mmol) and DBU (0.019 mL, 0.126 mmol). After 30 minutes, (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0, prepared as described in Example 35. ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.028 g, 0.084 mmol) was added along with DMF (0.4 ml). The reaction was stirred for 4 hours, then diluted with DMF, filtered and concentrated. The residue was purified by reverse phase HPLC using Phenomenex® Luna 5U 30x100 mm (10:90 ACN/H ₂ O to 90:10 ACN/H ₂ O, 0.1% TFA) (20% B starting, 14 min gradient). Purify (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6- Oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca- 1(18),2(6),4,14,16-pentaen-8-one (18.8 mg, 34%) was obtained as a white solid. MS(ESI) m/z: 659.03 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.81 (d, J=0.7 Hz, 1H), 8.18 (s, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.82 - 7.74 (m, 3H) , 7.70 (s, 1H), 7.64 - 7.56 (m, 3H), 7.42 - 7.36 (m, 1H), 6.49 (d, J=0.7 Hz, 1H), 5.83 (dd, J=12.9, 3.2 Hz, 1H) ), 2.50 (ddd, J=10.2, 6.8, 3.4 Hz, 1H), 2.35 (d, J=12.3 Hz, 1H), 2.15 - 2.06 (m, 1H), 1.94 - 1.85 (m, 1H), 1.65 - 1.51 (m, 2H), 1.31 - 1.20 (m, 1H), 1.16 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT = 9.40 min, purity = 100%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 15 nM.

Example 76

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5 Preparation of 15,17-hexaen-9-one

6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl] prepared as described in Intermediate 15 in CH ₃ CN (0.4 ml) phenyl} To a solution of pyrimidin-4-ol (0.035 g, 0.102 mmol) was added HATU (0.050 g, 0.132 mmol) and DBU (0.023 mL, 0.152 mmol). After 30 min, (10R,14S)-14-amino-10-methyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1 (19), prepared as described in Intermediate 38; 2(7),3,5,15,17-hexaen-9-one (0.030 g, 0.102 mmol) was added along with DMF (0.6 ml). After 18 hours, the reaction was diluted with DMF, filtered and concentrated. The residue was purified by preparative LCMS using (5:95 ACN/H ₂ O to 95:5 ACN/H ₂ O, 0.1% TFA) to give (10R,14S)-14-(4-{5- Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)- 10-methyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one (8.6 mg , 11.1%) was obtained. MS(ESI) m/z: 620.08 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.81 - 8.72 (m, 1H), 8.59 (d, J=4.3 Hz, 1H), 8.16 (s, 1H), 7.88 - 7.83 (m, 2H), 7.78 - 7.65 (m, 4H), 7.58 - 7.53 (m, 1H), 7.53 - 7.48 (m, 1H), 7.28 (d, J=7.6 Hz, 1H), 6.43 (s, 1H), 5.88 - 5.72 (m, 1H), 2.49 (br. s., 1H), 2.27 (d, J=10.4 Hz, 1H), 2.10 (d, J=10.1 Hz, 1H), 1.85 (d, J=8.9 Hz, 1H), 1.55 (d, J=9.8 Hz, 2H), 1.28 (br. s., 1H), 1.13 (d, J=6.7 Hz, 3H). Analytical HPLC (Method C) RT = 1.55 min, purity = 97%; Factor XIa Ki = 1.7 nM, plasma kallikrein Ki = 130 nM.

Example 77

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4, Preparation of 14,16-pentaen-8-one

6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidine- prepared as described in Intermediate 9 in CH ₃ CN (0.4 ml) To a solution of 4-ol (0.019 g, 0.060 mmol) was added HATU (0.030 g, 0.078 mmol) and DBU (0.014 mL, 0.090 mmol). After 30 min, (9R,13S)-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca prepared as described in Intermediate 42. -1(18),2(6),4,14,16-pentaen-8-one was added along with DMF (0.2 ml). After 18 hours, the reaction was diluted with DMF, filtered and concentrated. The residue was purified by reverse phase HPLC using Phenomenex® Luna 5U 30x100 mm (90:10 ACN/H ₂ O in 10:90 ACN/H ₂ O, 0.1% TFA) (20% B starting, 14 min gradient). Purify (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6 -dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,17-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,14,16-pentaen-8-one (11.9 mg, 27%) was obtained as an off-white solid. MS(ESI) m/z: 590.3 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ d 8.78 - 8.70 (m, 1H), 8.41 - 8.33 (m, 2H), 7.92 - 7.85 (m, 2H), 7.80 - 7.73 (m, 1H), 7.71 - 7.65 (m, 1H), 7.51 (s, 1H), 7.21 (dd, J=5.3, 1.8 Hz, 1H), 6.50 - 6.42 (m, 1H), 5.77 (dd, J=12.5, 3.1 Hz, 1H) , 4.23 - 4.16 (m, 3H), 2.69 - 2.58 (m, 1H), 2.41 (dd, J=7.5, 4.2 Hz, 1H), 2.22 - 2.09 (m, 1H), 2.07 - 1.96 (m, 1H) , 1.74 - 1.60 (m, 1H), 1.38 (d, J=7.7 Hz, 2H), 1.15 (d, J=7.0 Hz, 3H). Analytical HPLC (Method A) RT = 7.38 min, purity = 96%; Factor XIa Ki = 0.2 nM, plasma kallikrein Ki = 23 nM.

Example 78

(9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo [ _12.3.1.0 ^2,6 ]octadeca-1(18),2 Preparation of (6),4,14,16-pentaen-8-one

6-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]pyrimidin-4-ol (0.05 g, 0.142 mmol) in a small vial and To HATU (0.070 g, 0.184 mmol) was added DBU (0.032 mL, 0.213 mmol) in CH ₃ CN (0.8 ml). After 30 min, (9R,13S)-13-amino-3-( ^2H ₃ )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ² prepared as described in Intermediate 36. ^,6 ]Octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.043 g, 0.142 mmol) was added and the vial was rinsed with DMF (0.2 ml). After 18 hours, _{the reaction was diluted with DMF, filtered and purified by reverse phase HPLC with Phenomenex® Luna 5U 30x100 mm (10:90 MeOH/H 2 O} , 0.1% TFA) (20 % B start, 14 min gradient) to give (9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5 -chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1 _-yl}-3-(2H3 ⁾ methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (30 mg, 33%) was obtained as a white solid. This compound was used in the subsequent reaction, and a small amount (4 mg, white solid after freeze-drying) was purified using (95:5 AcN/H ₂ O in 5:95 AcN/H ₂ O, 10 mM NH ₄ OAc). Isolated by preparative LCMS. MS(ESI) m/z: 638.4 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.25 (s, 1H), 8.06 (s, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.68 - 7.59 (m, 2H), 7.56 - 7.43 ( m, 3H), 7.40 - 7.36 (m, 1H), 7.21 (d, J=7.5 Hz, 1H), 6.30 (s, 1H), 5.71 (dd, J=12.7, 3.2 Hz, 1H), 2.43 - 2.32 (m, 1H), 2.28 - 2.18 (m, 1H), 1.98 (d, J=12.3 Hz, 1H), 1.84 - 1.73 (m, 1H), 1.56 - 1.41 (m, 2H), 1.10 (br. s) ., 1H), 1.03 (d, J=6.8 Hz, 3H). Analytical HPLC (Method C) RT = 1.60 min, purity = 96%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 7 nM.

Example 79

(9R,13S)-13-(4-{5-chloro-2-[4-(pyrimidin-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6- Oxo-1,6-dihydropyrimidin _- 1-yl)-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl] prepared as described in Example 78 -6-oxo-1,6-dihydropyrimidin _- 1-yl}-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.014 g, 0.022 mmol), pyrimidin-2-ylboronic acid (2.59 mg, 0.021 mmol), and 2.0 M aqueous Na ₂ CO ₃ (0.033 mL, 0.066 mmol) was added to dioxane (0.6 ml) and the resulting solution was purged with a stream of Ar. Then, Pd(PPh ₃ ) ₄ (1.270 mg, 1.099 μmol) was added and the mixture was heated in the microwave at 120° C. for 30 min. The reaction was concentrated and the residue was diluted with DMF, filtered and re-concentrated. The residue was purified by preparative LCMS using (5:95 ACN/H ₂ O to 95:5 ACN/H ₂ O, 10 mM NH ₄ OAc) to give (9R,13S)-13-(4-{ 5-chloro-2-[4-(pyrimidin-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1 -yl)-3-( ^2H ₃ )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, 14,16-pentaen-8-one (2.5 mg, 25%) was obtained. MS(ESI) m/z: 636.08 (M+H) ⁺ .

^1H NMR (400MHz, CD ₃ OD) δ 9.16 - 9.11 (m, 2H), 9.06 (s, 1H), 8.75 - 8.65 (m, 1H), 8.02 (s, 1H), 7.85 - 7.77 (m, 1H) ), 7.71 - 7.63 (m, 1H), 7.63 - 7.58 (m, 2H), 7.45 - 7.35 (m, 3H), 7.16 (s, 1H), 6.37 - 6.30 (m, 1H), 5.69 (d, J =9.2 Hz, 1H), 2.35 (s, 1H), 2.18 (d, J=9.9 Hz, 1H), 1.95 (d, J=7.9 Hz, 1H), 1.73 (s, 1H), 1.44 (d, J =9.5 Hz, 2H), 1.19 (m, 1H), 1.02 (d, J=6.8 Hz, 3H). Analytical HPLC (Method C) RT = 1.43 min, purity = 95%; Factor XIa Ki = 1.0 nM, plasma kallikrein Ki = 150 nM.

Example 80

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4,10-dimethyl-3,8-diazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3 Preparation of 5,15,17-hexaen-9-one

80A. tert-Butyl N-[(1S)-1-[3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]but-3-en-1-yl]car Preparation of Bamate

tert-butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (2.6 g, 7.97 mmol), 5 in RBF in dioxane (35 ml) ,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane (1.980 g, 8.77 mmol), and KOAc (2.347 g, 23.91 mmol) were added. The mixture was purged with Ar for 10 min, then PdCl ₂ (dppf)-DCM adduct (0.325 g, 0.398 mmol) was added and the reaction was stirred for 4 h at 90° C. The reaction was mixed with EtOAc (50 ml). Partitioned between water (40 ml). The organic layer was separated, washed with water (15 ml), brine (30 ml), dried over MgSO ₄ , filtered and concentrated. The residue was subjected to normal phase chromatography. purified using hexane and EtOAc as eluents to give tert-butyl N-[(1S)-1-[3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl] But-3-en-1-yl]carbamate (2.62 g, 92%) was obtained as a white solid, MS(ESI) m/z: 292.08 (M+H) ⁺ .

80B. Preparation of tert-butyl N-[(1S)-1-[3-(3-amino-6-methylpyridin-2-yl)phenyl]but-3-en-1-yl]carbamate

tert-Butyl N-[(1S)-1-[3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]but-3-en-1-yl]car Bamate (0.67 g, 1.865 mmol), 2-bromo-6-methylpyridin-3-amine (0.349 g, 1.865 mmol), and 2 M aqueous Na ₂ CO ₃ (4 mL, 8.00 mmol) were dissolved in dioxane ( 9 ml) and the solution was purged with a stream of Ar for 10 min. Pd(PPh ₃ ) ₄ (0.108 g, 0.093 mmol) was added, and the mixture was irradiated in a microwave at 120°C for 30 minutes. The reaction was quenched with water (20 ml) and extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with brine (15 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using DCM and 0-10% MeOH as eluent to give tert-butyl N-[(1S)-1-[3-(3-amino-6-methylpyridin-2-yl )Phenyl]but-3-en-1-yl]carbamate (0.94 g, 100%, 70% purity) was obtained as a brown oil. MS(ESI) m/z: 354.5 (M+H) ⁺ .

80C. tert-Butyl N-[(1S)-1-(3-{6-methyl-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3- Preparation of en-1-yl]carbamate

tert-Butyl N-[(1S)-1-[3-(3-amino-6-methylpyridin-2-yl)phenyl]but-3-en-1-yl]carbamate in EtOAc (0.58 ml) To a solution of (0.65 g, 1.83 mmol) was added (R)-2-methylbut-3-enoic acid (0.239 g, 2.391 mmol) prepared as described in Intermediate 2 in 0.3 ml EtOAc. The resulting solution was cooled to 0°C and pyridine (0.446 ml, 5.52 mmol) and 50% EtOAc solution of T3P® (2.189 ml, 3.68 mmol) were added. After 3 hours, the reaction was quenched with saturated NaHCO ₃ (15 ml) and extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (15 ml) and dried (MgSO ₄ ). The mixture was filtered, concentrated and the residue was purified by normal phase chromatography using DCM and 0-10% MeOH as eluent to give tert-butyl N-[(1S)-1-(3-{6-methyl- 3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate (0.65 g, 82%) was prepared as a yellow-brown foam. Obtained. MS(ESI) m/z: 436.08 (M+H) ⁺ .

^1H NMR (500MHz, CDCl ₃ ) δ 8.56 (d, J=8.5 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.42 (s, 1H), 7.37 (d, J=1.4 Hz, 2H), 7.17 (d, J=8.5 Hz, 1H), 5.90 - 5.67 (m, 2H), 5.22 - 5.03 (m, 4H), 5.00 - 4.75 (m, 3H), 3.05 (t, J=7.3 Hz, 1H) , 2.62 (br. s. and m, 4H), 1.50 - 1.39 (m, 9H), 1.28 (d, J=7.2 Hz, 3H).

80D. tert-Butyl N-[(10R,11E,14S)-4,10-dimethyl-9-oxo-3,8-diazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2( 7), 3,5,11,15,17-heptaen-14-yl] Preparation of carbamate

tert-Butyl N-[(1S)-1-(3-{6-methyl-3-[(2R)-2-methylbut-3-enamido]pyridine-2- in degassed DCE (20 ml) {{phenyl)but-3-en-1-yl]carbamate (0.2 g, 0.459 mmol) was added to a solution of second generation Grubbs catalyst (0.156 g, 0.184 mmol), and the resulting reaction mixture was purified using a micro Heated at 120°C for 30 minutes in a wave. The reaction mixture was purified directly by normal phase chromatography using DCM and 0-10% MeOH as eluent to give tert-butyl N-[(10R,11E,14S)-4,10-dimethyl-9-oxo-3,8. -diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.19g, 100%) was obtained as a dark solid. MS(ESI) m/z: 408.08 (M+H) ⁺ .

80E. (10R,14S)-14-amino-4,10-dimethyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2(7),3,5,15 , Preparation of 17-hexaen-9-one

tert-Butyl N-[(10R,11E,14S)-4,10-dimethyl-9-oxo-3,8-diazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2( 7),3,5,11,15,17-heptaen-14-yl]carbamate (0.187 g, 0.459 mmol) was hydrogenated in EtOH (3 ml) at 20-30 psi in the presence of PtO ₂ . After 4 hours, the reaction mixture was filtered through Celite® and concentrated to give a dark solid (MS(ESI) m/z: 410.3 (M+H) ⁺ ), which was then washed with 4 N HCl in dioxane (2 ml) and deprotected with MeOH (2 ml). The resulting HCl salt was dissolved in DCM/MeOH and passed through a basic cartridge to obtain (10R,14S)-14-amino-4,10-dimethyl-3,8-diazatricyclo[13.3.1.0 ^2, A crude dark solid containing ⁷ ]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one (0.16 g, 118%) was obtained, which was carried to the next step. It was used without purification. MS(ESI) m/z: 310.3 (M+H) ⁺ .

80F. (10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4,10-dimethyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2(7),3 Preparation of 5,15,17-hexaen-9-one

6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidine prepared as described in Intermediate 15 in a small vial. To -4-ol (0.033 g, 0.097 mmol), and HATU (0.048 g, 0.126 mmol) was added DBU (0.022 mL, 0.145 mmol) in ACN (0.4 ml). After 30 minutes, (10R,14S)-14-amino-4,10-dimethyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3 ,5,15,17-hexaen-9-one (0.033 g, 0.097 mmol) was added along with DMF (0.2 ml). The reaction was stirred for 18 hours. The reaction was diluted with DMF, filtered and purified by preparative LCMS using (5:95 ACN/H ₂ O to 95:5 ACN/H ₂ O, 10 mM NH ₄ OAc) to give (10R,14S). -14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-di Hydropyrimidin-1-yl)-4,10-dimethyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2(7),3,5,15, 17-Hexaen-9-one (5.8 mg, 7.7% yield) was obtained as a white solid. MS(ESI) m/z: 634.4 (M+H) ⁺ .

^1H NMR (500MHz, CD ₃ OD) δ 8.75 (s, 1H), 8.12 (s, 1H), 7.86 - 7.82 (m, 2H), 7.77 - 7.64 (m, 3H), 7.62 - 7.54 (m, 2H) ), 7.34 (d, J=8.2 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 6.43 (s, 1H), 5.86 - 5.73 (m, 1H), 2.61 (s, 3H), 2.45 (br. s., 1H), 2.26 (d, J=9.5 Hz, 1H), 2.11 (br. s., 1H), 1.82 (br. s., 1H), 1.64 - 1.49 (m, 2H), 1.28 - 1.21 (m, 1H), 1.13 (d, J=6.7 Hz, 3H). Analytical HPLC (Method C) RT = 1.54 min, purity = 97%; Factor XIa Ki = 2.2 nM, plasma kallikrein Ki = 260 nM.

Example 81

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-5-methoxy-10-methyl-3,8-diazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7 ), 3,5,15,17-hexaen-9-one production

81A. Preparation of tert-butyl N-[(1S)-1-[3-(3-amino-5-methoxypyridin-2-yl)phenyl]but-3-en-1-yl]carbamate

tert-Butyl N-[(1S)-1-[3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]but-3-en-1-yl]car Bamate (0.348 g, 0.969 mmol), 2-bromo-5-methoxypyridin-3-amine (0.197 g, 0.969 mmol), and 2.0 M aqueous Na ₂ CO ₃ (2.422 mL, 4.84 mmol) were dissolved in dioxane. (8 ml) and the solution was purged with a stream of Ar for 10 min. Pd(PPh ₃ ) ₄ (0.056 g, 0.048 mmol) was added, and the mixture was irradiated in a microwave at 120°C for 30 minutes. The reaction was quenched with water (20 ml) and extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with brine (15 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using DCM and 0-10% MeOH as eluent to give tert-butyl N-[(1S)-1-[3-(3-amino-5-methoxypyridine-2- 1) Phenyl]but-3-en-1-yl]carbamate (0.391 g, 100%) was obtained as a tan foam. MS(ESI) m/z: 370.08 (M+H) ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.89 (d, J=2.5 Hz, 1H), 7.60 - 7.52 (m, 2H), 7.45 (t, J=7.6 Hz, 1H), 7.33 - 7.29 (m, 1H) ), 6.62 (d, J=2.5 Hz, 1H), 5.73 (ddt, J=17.1, 10.1, 7.0 Hz, 1H), 5.21 - 5.06 (m, 2H), 4.93 (br. s., 1H), 4.81 (br. s., 1H), 3.92 - 3.86 (m, 4H), 3.77 - 3.71 (m, 1H), 2.64 - 2.52 (m, 2H), 1.44 (br. s., 9H).

81B. tert-Butyl N-[(1S)-1-(3-{5-methoxy-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3 Preparation of -en-1-yl]carbamate.

tert-Butyl N-[(1S)-1-[3-(3-amino-5-methoxypyridin-2-yl)phenyl]but-3-en-1-yl]carbamate (0.358 g, 0.972 mmol) was added (R)-2-methylbut-3-enoic acid (0.126 g, 1.263 mmol) prepared as described in Intermediate 2 in EtOAc (3 ml). The resulting solution was cooled to 0°C. Pyridine (0.236 ml, 2.91 mmol) and 50% EtOAc solution of T3P® (1.157 ml, 1.943 mmol) were added. The reaction was partitioned between saturated NaHCO ₃ (10 ml) and EtOAc (20 ml). The aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using heptane and EtOAc as eluents to give tert-butyl N-[(1S)-1-(3-{5-methoxy-3-[(2R)-2-methylbut -3-enamido]pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate (0.347 g, 79%) was obtained as a white foam. MS(ESI) m/z: 452.08 (M+H) ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.47 (d, J=2.8 Hz, 1H), 8.16 (d, J=2.8 Hz, 1H), 7.65 (br. s., 1H), 7.53 - 7.46 (m, 1H), 7.46 - 7.41 (m, 1H), 7.37 (dt, J=7.5, 1.9 Hz, 2H), 5.86 - 5.65 (m, 2H), 5.19 - 5.07 (m, 4H), 4.93 (br. s. , 1H), 4.82 (br. s., 1H), 3.93 (s, 3H), 3.07 (quin, J=7.3 Hz, 1H), 2.62 - 2.51 (m, 2H), 1.50 - 1.41 (m, 9H) , 1.32 - 1.29 (m, 3H).

81C. tert-Butyl N-[(10R,11E,14S)-5-methoxy-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19) ,2(7),3,5,11,15,17-heptaen-14-yl]Manufacture of carbamate

tert-Butyl N-[(1S)-1-(3-{5-methoxy-3-[(2R) in degassed DCE (20 ml) in the presence of second generation Grubbs catalyst (0.107 g, 0.126 mmol) )-2-methylbut-3-enamido]pyridin-2-yl} phenyl)but-3-en-1-yl]carbamate (0.189 g, 0.419 mmol) was heated to 120°C in a microwave. Heated for 30 minutes. The reaction mixture was purified directly by normal phase chromatography using DCM and 0-10% MeOH as eluent to give tert-butyl N-[(10R,11E,14S)-5-methoxy-10-methyl-9-oxo- 3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate ( 0.17 g, 96%) was obtained as a dark brown oil. MS(ESI) m/z: 424.1 (M+H) ⁺ .

81D. (10R,14S)-14-amino-5-methoxy-10-methyl-3,8-diazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3, Preparation of 5,15,17-hexaen-9-one

tert-Butyl N-[(10R,11E,14S)-5-methoxy-10-methyl-9-oxo-3,8-diazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19) ,2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.177 g, 0.418 mmol) was dissolved in EtOH (3) over 8 h in the presence of PtO ₂ (20 mg). ml). The resulting thick sludge was filtered through Celite® and rinsed with DCM, MeOH and EtOH to yield 0.121 g of a dark solid. MS(ESI) m/z: 426.4 (M+H) ⁺ . Deprotection was performed with 4 N HCl (2 ml) in dioxane in MeOH (4 ml) over 3 hours. The reaction mixture was concentrated, the residue was taken up in DCM/MeOH and filtered through a basic cartridge (10R,14S)-14-amino-5-methoxy-10-methyl-3,8-diazatricyclo[13.3 .1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one was obtained as a dark solid (0.108 g, 79%). MS(ESI) m/z: 326.4 (M+H) ⁺ .

81E. (10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-5-methoxy-10-methyl-3,8-diazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7) ), Preparation of 3,5,15,17-hexaen-9-one

6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidine prepared as described in Intermediate 15 in a small vial. To -4-ol (0.032 g, 0.092 mmol), and HATU (0.046 g, 0.120 mmol) was added DBU (0.021 mL, 0.138 mmol) in ACN (0.4 ml). After 30 minutes, (10R,14S)-14-amino-5-methoxy-10-methyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7) ),3,5,15,17-hexaen-9-one (0.030 g, 0.092 mmol) was added along with DMF (0.4 ml). After 18 hours, the reaction was diluted with DMF, filtered and concentrated. The residue was purified by reverse phase HPLC using Phenomenex® Luna 5U 30x100 mm (90:10 ACN/H ₂ O in 10:90 ACN/H ₂ O, 0.1% TFA) (20% B starting, 14 min gradient). Purified twice to obtain (10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}- 6-oxo-1,6-dihydropyrimidin-1-yl)-5-methoxy-10-methyl-3,8-diazatricyclo [13.3.1.0 ^2,7 ] nonadeca-1 (19) ,2(7),3,5,15,17-hexaen-9-one (3.7 mg, 4.8%) was obtained as a white solid. MS(ESI) m/z: 650.3 (M+H) ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.82 (d, J=0.7 Hz, 1H), 8.39 (d, J=2.6 Hz, 1H), 8.25 (s, 1H), 7.89 (d, J=2.2 Hz) , 1H), 7.86 (s, 1H), 7.80 - 7.74 (m, 1H), 7.71 - 7.63 (m, 2H), 7.62 - 7.55 (m, 2H), 7.29 (d, J=7.9 Hz, 1H), 6.47 (d, J=0.7 Hz, 1H), 5.81 (dd, J=13.0, 3.5 Hz, 1H), 4.03 - 4.01 (m, 3H), 2.60 - 2.49 (m, 1H), 2.34 - 2.26 (m, 1H), 2.18 - 2.08 (m, 1H), 1.94 - 1.85 (m, 1H), 1.62 - 1.46 (m, 2H), 1.33 (d, J=9.7 Hz, 1H), 1.15 (d, J=6.8 Hz) , 3H). Analytical HPLC (Method A) RT = 8.44, purity = 93%; Factor XIa Ki = 22 nM, plasma kallikrein Ki = 950 nM.

Example 82

(10R,14S)-5-Chloro-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}- 6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7) Preparation of 3,5,15,17-hexaen-9-one

82A. Preparation of tert-butyl N-[(1S)-1-[3-(3-amino-5-chloropyridin-2-yl)phenyl]but-3-en-1-yl]carbamate

tert-Butyl N-[(1S)-1-[3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]but-3-en-1-yl]car Bamate (0.339 g, 0.944 mmol), 2-bromo-5-chloropyridin-3-amine (0.196 g, 0.944 mmol), and 2.0 M aqueous Na ₂ CO ₃ (2.36 mL, 4.72 mmol) were dissolved in dioxane ( 8 ml) and the resulting solution was purged with a stream of Ar for 10 min. Pd(PPh ₃ ) ₄ (0.055 g, 0.047 mmol) was added, and the mixture was irradiated in a microwave at 120° C. for 30 minutes. The reaction was quenched with water (20 ml) and extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with brine (15 ml), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using DCM and 0-10% MeOH as eluent to give tert-butyl N-[(1S)-1-[3-(3-amino-5-chloropyridin-2-yl ) phenyl]but-3-en-1-yl]carbamate (0.375 g, 106%) was obtained as a tan foam. MS(ESI) m/z: 374.3 (M+H) ⁺ .

^1H NMR (500MHz, CDCl ₃ ) δ 8.08 (d, J=2.2 Hz, 1H), 7.60 - 7.52 (m, 2H), 7.48 - 7.43 (m, 1H), 7.34 (d, J=7.7 Hz, 1H) ), 7.07 (d, J=1.9 Hz, 1H), 5.72 (ddt, J=17.1, 10.1, 7.0 Hz, 1H), 5.21 - 5.09 (m, 2H), 4.93 (br. s., 1H), 4.81 (br. s., 1H), 3.94 (br. s., 2H), 2.63 - 2.51 (m, 2H), 1.43 (br. s., 9H).

82B. tert-Butyl N-[(1S)-1-(3-{5-chloro-3-[(2R)-2-methylbut-3-enamido]pyridin-2-yl}phenyl)but-3- Preparation of en-1-yl]carbamate

tert-Butyl N-[(1S)-1-[3-(3-amino-5-chloropyridin-2-yl)phenyl]but-3-en-1-yl]carbamate (0.358 g, 0.958 mmol ) was added (R)-2-methylbut-3-enoic acid (0.125 g, 1.245 mmol) prepared as described in Intermediate 2 in 3 ml EtOAc and the resulting solution was cooled to 0°C. Then pyridine (0.232 ml, 2.87 mmol) and 50% EtOAc solution of T3P® (1.140 ml, 1.915 mmol) were added. After 4 hours, the reaction was partitioned using saturated NaHCO ₃ (10 ml) and EtOAc (10 ml). The aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with brine (10 ml), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using heptane and EtOAc as eluents to give tert-butyl N-[(1S)-1-(3-{5-chloro-3-[(2R)-2-methylbut- 3-enamido]pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate (0.31 g, 71%) was obtained as a white foam. MS(ESI) m/z: 456.08 (M+H) ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.88 (d, J=2.2 Hz, 1H), 8.38 (d, J=2.2 Hz, 1H), 7.65 (br. s., 1H), 7.56 - 7.49 (m, 1H), 7.45 - 7.40 (m, 2H), 7.39 - 7.33 (m, 1H), 5.82 - 5.66 (m, 2H), 5.21 - 5.11 (m, 2H), 5.11 - 5.06 (m, 2H), 4.93 ( br. s., 1H), 4.82 (br. s., 1H), 3.08 (quin, J=7.2 Hz, 1H), 2.64 - 2.50 (m, 2H), 1.46 - 1.41 (m, 9H), 1.30 ( d, J=7.2 Hz, 3H).

82C. tert-butyl N-[(10R,11E,14S)-5-chloro-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19), Preparation of 2(7),3,5,11,15,17-heptaen-14-yl]carbamate

Second generation Grubbs catalyst (0.107 g, 0.126 mmol) and tert-butyl N-[(1S)-1-(3-{5-chloro-3-[(2R)-2 in degassed DCE (20 ml) -Methylbut-3-enamido]pyridin-2-yl}phenyl)but-3-en-1-yl]carbamate (0.191 g, 0.419 mmol) was heated in the microwave at 120°C for 30 minutes. Heated. The reaction mixture was concentrated and the crude material was purified directly by normal phase chromatography using DCM and 0-10% MeOH as eluent to give tert-butyl N-[(10R,11E,14S)-5-chloro-10-methyl. -9-oxo-3,8-diazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl ]Carbamate (0.17 g, 95%) was obtained as a dark brown oil. MS(ESI) m/z: 428.2 (M+H) ⁺ .

82D. (10R,14S)-14-amino-5-chloro-10-methyl-3,8-diazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5 Preparation of 15,17-hexaen-9-one

tert-butyl N-[(10R,11E,14S)-5-chloro-10-methyl-9-oxo-3,8-diazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19), 2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.17 g, 0.397 mmol) was incubated in EtOH (3 ml) in the presence of PtO ₂ (20 mg) for 8 h. hydrogenated for a while. MS(ESI) m/z: 430.3 (M+H) ⁺ . The thick sludge was filtered through Celite® and rinsed with DCM/MeOH/EtOH to give 0.169 g of a dark solid. Deprotection was performed with 4 N HCl (2 ml) and MeOH (2 ml) in dioxane over 4 hours. The solution was then concentrated, the residue was dissolved in DCM/MeOH and passed through a basic cartridge to (10R,14S)-14-amino-5-chloro-10-methyl-3,8-diazatricyclo [13.3 .1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one was obtained as crude product (0.159 g, 121%), which was purified as is. ' was used. MS(ESI) m/z: 330.08 (M+H) ⁺ .

82E. (10R,14S)-5-Chloro-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}- 6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7) Preparation of 3,5,15,17-hexaen-9-one

HATU (0.045 g, 0.118 mmol) in a small vial and 6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole prepared as described in Intermediate 15. To -1-yl]phenyl}pyrimidin-4-ol (0.031 g, 0.091 mmol) was added DBU (0.021 mL, 0.136 mmol) in CH ₃ CN (0.4 ml). After 30 minutes, tert-butyl N-[(10R,11E,14S)-5-chloro-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1 (19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.030 g, 0.091 mmol) was added along with DMF (0.4 ml). After 18 hours, the reaction was diluted with DMF, filtered and concentrated. The residue was purified by reverse phase HPLC using Phenomenex® Luna 5U 30x100 mm (10:90 ACN/H ₂ O to 90:10 ACN/H ₂ O, 0.1% TFA) (20% B starting, 14 min gradient). Purified twice to obtain (10R,14S)-5-chloro-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl ]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1 (19), 2(7),3,5,15,17-hexaen-9-one (3.0 mg, 4.2% yield) was obtained as a tan solid. MS(ESI) m/z: 654.3 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.81 (d, J=0.7 Hz, 1H), 8.67 - 8.62 (m, 1H), 8.23 (s, 1H), 7.93 - 7.84 (m, 3H), 7.79 - 7.67 (m, 3H), 7.63 - 7.54 (m, 1H), 7.29 (d, J=7.9 Hz, 1H), 6.47 (d, J=0.9 Hz, 1H), 5.82 (dd, J=12.9, 3.6 Hz) , 1H), 2.58 - 2.48 (m, 1H), 2.40 - 2.24 (m, 1H), 2.11 (d, J=9.7 Hz, 1H), 1.99 - 1.87 (m, 1H), 1.55 (d, J=9.0 Hz, 2H), 1.33 (d, J=9.7 Hz, 1H), 1.15 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT = 9.88 min, purity = 98%; Factor XIa Ki = 3.5 nM, plasma kallikrein Ki = 240 nM.

Example 83

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,16-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4, Preparation of 14,16-pentaen-8-one

83A. tert-Butyl N-[(1S)-1-[5-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-3-yl]but-3-en-1-yl]car Preparation of Bamate

tert-Butyl N-[(1S)-1-(5-bromopyridin-3-yl)but-3-en-1-yl]carba prepared as described in Intermediate 26 in dioxane (10 ml) To a solution of mate (1.0 g, 3.06 mmol) was added 1-methyl-4-nitro-1H-pyrazole (0.427 g, 3.36 mmol), di(adamantan-1-yl)(butyl)phosphine (0.164 g, 0.458 mmol), K ₂ CO ₃ (1.267 g, 9.17 mmol) and pivalic acid (0.106 ml, 0.917 mmol) were added. The reaction mixture was purged with Ar. Pd(OAc) ₂ (0.069 g, 0.306 mmol) was added and the solution was stirred at 100°C. After 4 hours, the reaction was quenched with water (20 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using heptane and EtOAc as eluents to give tert-butyl N-[(1S)-1-[5-(1-methyl-4-nitro-1H-pyrazol-5-yl )Pyridin-3-yl]but-3-en-1-yl]carbamate (0.85 g, 74%) was obtained as a white foam. MS(ESI) m/z: 374.5 (M+H) ⁺ .

^1H NMR (500MHz, CDCl ₃ ) δ 8.74 (d, J=1.9 Hz, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.25 (s, 1H), 7.72 (t, J=1.9 Hz, 1H), 5.73 (ddt, J=17.1, 10.2, 7.2 Hz, 1H), 5.26 - 5.17 (m, 2H), 4.99 (br. s., 1H), 4.93 - 4.84 (m, 1H), 3.80 (s) , 3H), 2.75 - 2.52 (m, 2H), 1.43 (br. s., 9H).

83B. tert-Butyl N-[(1S)-1-[5-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-3-yl]but-3-en-1-yl]car Preparation of Bamate

tert-Butyl N-[(1S)-1-[5-(1-methyl-4-nitro-1H-pyrazol-5-yl) pyridine- in acetone (60 ml)/water (15 ml) at 0°C. To a solution of 3-yl]but-3-en-1-yl]carbamate (0.85 g, 2.276) was added NH ₄ Cl (0.609 g, 11.38 mmol) and Zn (1.488 g, 22.76 mmol). The ice bath was removed and the reaction was stirred for 18 hours. The reaction was filtered through paper and partitioned between water (20 ml) and EtOAc (75 ml). The aqueous layer was extracted with EtOAc (2 x 50 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using hexane and EtOAc as eluents to give tert-butyl N-[(1S)-1-[5-(4-amino-1-methyl-1H-pyrazol-5-yl )Pyridin-3-yl]but-3-en-1-yl]carbamate (0.64 g, 65% yield) was obtained. MS(ESI) m/z: 344.5 (M+H) ⁺ .

83C. tert-Butyl N-[(1S)-1-(5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyridine- 3-day) Preparation of but-3-en-1-yl]carbamate

tert-Butyl N-[(1S)-1-(5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazole- in EtOAc (4 ml) 5-yl}pyridin-3-yl) but-3-en-1-yl] (R)-2 prepared as described in Intermediate 2 in a solution of carbamate (0.5 g, 1.45 mmol) in 0.3 ml EtOAc. A solution of -methylbut-3-enoic acid (0.189 g, 1.893 mmol) was added. The reaction mixture was cooled to 0°C and pyridine (0.353 ml, 4.37 mmol) and 50% EtOAc solution of T3P® (1.733 ml, 2.91 mmol) were added. After 3 hours, the reaction was partitioned between saturated NaHCO ₃ (15 ml) and EtOAc (20 ml). The aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using DCM and 0-10% MeOH as eluent to give tert-butyl N-[(1S)-1-(5-{1-methyl-4-[(2R)-2 -methylbut-3-enamido]-1H-pyrazol-5-yl}pyridin-3-yl)but-3-en-1-yl]carbamate (0.48 g, 77% yield) as a pink solid. It was obtained as. MS(ESI) m/z: 426.5 (M+H) ⁺ .

^1H NMR (500MHz, CDCl ₃ ) δ 8.66 (d, J=2.2 Hz, 1H), 8.51 (d, J=1.9 Hz, 1H), 7.99 (s, 1H), 7.62 (t, J=2.1 Hz, 1H), 6.95 (br. s., 1H), 5.91 (ddd, J=17.2, 10.0, 8.0 Hz, 1H), 5.79 - 5.66 (m, 1H), 5.25 - 5.13 (m, 4H), 4.95 (br s., 1H), 4.82 (br. s., 1H), 3.85 - 3.77 (m, 3H), 3.10 (quin, J=7.2 Hz, 1H), 2.68 - 2.51 (m, 2H), 1.50 - 1.37 (m, 9H), 1.37 - 1.29 (m, 3H).

83D. tert-Butyl N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,16-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18 ), 2(6),4,10,14,16-hexaen-13-yl] Preparation of carbamate

tert-Butyl N-[(1S)-1-(5-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazole- in DCM (90 ml) 5-yl} pyridin-3-yl)but-3-en-1-yl]to a solution of carbamate (0.153 g, 0.36 mmol) was added pTsOH·H ₂ O (0.075 g, 0.396 mmol) and the mixture was degassed for 10 minutes and then heated to 40°C for 1 hour. Second generation Grubbs catalyst (0.122 g, 0.144 mmol) was added and the reaction was heated at 40° C. for 24 hours. The reaction was quenched with saturated NaHCO ₃ (15 ml) and extracted with DCM (3 x 20 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using DCM and MeOH as eluents to give tert-butyl N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,16- Tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (20 mg, 14%) was obtained as a brown solid. MS(ESI) m/z: 398.2 (M+H) ⁺ .

^1H NMR (500MHz, CDCl ₃ ) δ 8.60 (s, 1H), 7.57 (s, 1H), 7.25 - 7.17 (m, 1H), 6.98 (s, 1H), 6.52 (br. s., 1H), 5.78 - 5.65 (m, 1H), 5.14 (br. s., 1H), 5.04 - 4.96 (m, 1H), 4.79 (br. s., 1H), 3.97 (s, 3H), 3.85 - 3.74 (m) , 1H), 3.06 (br. s., 1H), 2.61 (br. s., 4H), 1.46 (br. s., 9H), 1.30 - 1.23 (m, 3H).

83E. (9R,13S)-13-amino-3,9-dimethyl-3,4,7,16-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 Preparation of ,14,16-pentaen-8-one

tert-Butyl N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,16-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18 ),2(6),4,10,14,16-hexaen-13-yl]carbamate (20 mg, 0.050 mmol) was reacted with EtOH (3 ml) at 55 psi in the presence of PtO ₂ (4 mg). hydrogenated in the process. After 4 hours, the reaction mixture was filtered through Celite® and concentrated to give 16 mg of a dark solid (MS(ESI) m/z: 400.08 (M+H) ⁺ ) which was then washed with 4 N HCl in dioxane. (1 ml) and MeOH (1 ml). After 3 hours, the mixture was concentrated and the resulting HCl salt was dissolved in DCM/MeOH and passed through a basic cartridge to give (9R,13S)-13-amino-3,9-dimethyl-3,4,7,16- Tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (15 mg, 100%) was obtained as a dark solid. .

83F. (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,16-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4, Preparation of 14,16-pentaen-8-one

6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol (prepared as described in Intermediate 15 in small vials) To 0.015 g, 0.050 mmol), and HATU (0.025 g, 0.065 mmol) was added DBU (0.011 mL, 0.075 mmol) in CH ₃ CN (0.4 ml). After 30 minutes, (9R,13S)-13-amino-3,9-dimethyl-3,4,7,16-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2( 6),4,14,16-pentaen-8-one (0.015 g, 0.050 mmol) was added along with DMF (0.2 ml). After 18 hours, the reaction was diluted with DMF, filtered and purified by reverse phase HPLC with Phenomenex® Luna 5U 30x100 mm (10:90 ACN/H ₂ O in 90:10 ACN/H ₂ O, 0.1% TFA) (20 % B start, 14 min gradient) to give (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl )phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,16-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one (4.1 mg, 11%) was obtained as an off-white solid. MS(ESI) m/z: 590.3 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.83 (d, J=1.8 Hz, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.42 - 8.34 (m, 2H), 8.30 (s, 1H) , 7.95 - 7.86 (m, 1H), 7.81 - 7.72 (m, 1H), 7.69 - 7.63 (m, 1H), 7.60 - 7.53 (m, 1H), 6.49 - 6.42 (m, 1H), 5.79 (dd, J=13.0, 3.1 Hz, 1H), 4.13 (s, 3H), 2.56 - 2.45 (m, 2H), 2.24 - 2.14 (m, 1H), 1.89 (br. s., 1H), 1.65 - 1.53 (m , 2H), 1.23 - 1.14 (m, 3H), 1.10 (br. s., 1H). Analytical HPLC (Method A) rt = 6.29 min, purity = 98%; Factor XIa Ki = 0.2 nM, plasma kallikrein Ki = 43 nM.

Example 84

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18 ), 2(6),4,14,16-pentaene-16-carboxamide production

84A. Preparation of 3-bromo-5-[(1E)-{[(R)-2-methylpropane-2-sulfinyl]imino}methyl]benzamide

3-Formylbenzonitrile (3.49 g, 26.6 mmol) in concentrated H ₂ SO ₄ (12 ml) was heated to 60° C. and NBS (5.68 g, 31.9 mmol) was added in 3 portions. The reaction was stirred for 2 hours. The reaction was quenched by pouring into ice water. The product was filtered and dried. The collected crude product was used 'as is' in the subsequent steps. The crude material was combined with (R)-2-methylpropane-2-sulfinamide (1.382 g, 11.40 mmol), Cs ₂ CO ₃ (5.57 g, 17.10 mmol) in DCM (57.0 ml) and stirred for 18 hours. The reaction thickened to a gel was diluted with DCM and stirring resumed for 3 hours. The reaction was partitioned between brine (40 ml) and DCM (50 ml). The insoluble gel was filtered. The aqueous layer was extracted with DCM (2 x 20 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using heptane and EtOAc as eluents to give 3-bromo-5-[(1E)-{[(R)-2-methylpropane-2-sulfinyl]imino}methyl. ]Benzamide (3.3 g) was obtained.

^1H NMR (400MHz, DMSO-d ₆ ) δ 8.58 (s, 1H), 8.42 (s, 1H), 8.34 (br. s., 1H), 8.26 (s, 2H), 7.68 (br. s., 1H), 1.20 (s, 9H).

84B. Preparation of 3-bromo-5-[(1S)-1-{[(R)-2-methylpropane-2-sulfinyl]amino}but-3-en-1-yl]benzamide

In to 3-bromo-5-[(1E)-{[(R)-2-methylpropane-2-sulfinyl]imino}methyl]benzamide (3.3 g, 9.96 mmol) in THF (75 ml) (1.716 g, 14.94 mmol) and 3-bromoprop-1-ene (1.30 ml, 14.94 mmol) were added. The reaction was stirred at room temperature. After 72 hours, the reaction became a gray suspension and LCMS showed that it was not complete. An additional 4 g of In and 2.6 ml of 3-bromoprop-1-ene were added. After an additional week, the reaction was filtered and the filtrate was concentrated to give the crude 3-bromo-5-[(1S)-1-{[(R)-2-methylpropane-2-sulfinyl]amino}but- 4 g of 3-en-1-yl]benzamide were obtained. MS(ESI) m/z: 373-375.1 (M+H) ⁺ .

84C. Preparation of tert-butyl N-[(1S)-1-(3-bromo-5-carbamoylphenyl)but-3-en-1-yl] carbamate

(1:1) 3-Bromo-5-[(1S)-1-{[(R)-2-methylpropane-2-sulfinyl]amino}but-3- in dioxane/MeOH (50 ml) To en-1-yl]benzamide (3.7 g, 9.91 mmol) was added 15 ml of concentrated HCl. The reaction was stirred for 24 hours and then concentrated. The residue was dissolved in DCM (50 ml) and cooled to 0°C. TEA (8.29 ml, 59.5 mmol) and BOC ₂ O (2.301 ml, 9.91 mmol) were added. Additional 1 N NaOH was added to ensure that the reaction was basic. After 24 hours, the thick reaction was filtered to yield a sticky solid. The sticky solid and both filtrates were combined and partitioned between water (100 ml) and EtOAc (150 ml). The aqueous layer was extracted with EtOAc (2 x 50 ml). The combined organic layers were washed with brine (50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using hexane and EtOAc as eluents to give tert-butyl N-[(1S)-1-(3-bromo-5-carbamoylphenyl)but-3-en-1. -yl] carbamate (0.92 g, 25%) was obtained. MS(ESI) m/z: 311-313.3 (M+Ht-butyl) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 - 7.79 (m, 1H), 7.74 (br. s., 1H), 7.56 (t, J=1.5 Hz, 1H), 6.66 (br. s., 1H) , 6.40 (br. s., 1H), 5.74 - 5.59 (m, 1H), 5.28 - 5.19 (m, 1H), 5.17 - 5.12 (m, 1H), 4.71 (br. s., 1H), 2.57 - 2.45 (m, 3H), 1.49 - 1.34 (m, 9H).

84D. tert-Butyl N-[(1S)-1-{3-carbamoyl-5-[1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl]phenyl}but-3- Preparation of en-1-yl]carbamate

(S)-tert-butyl (1-(3-bromo-5-carbamoylphenyl)but-3-en-1-yl)carbamate (0.2 g, 0.542 mmol) in dioxane (3 ml) In a solution of 1-(difluoromethyl)-4-nitro-1H-pyrazole (0.106 g, 0.650 mmol), di(adamantan-1-yl)(butyl)phosphine (0.029 g, 0.081 mmol) , K ₂ CO ₃ (0.225 g, 1.625 mmol) and pivalic acid (0.019 ml, 0.162 mmol) were added. The reaction was purged with Ar. Afterwards, Pd(OAc) ₂ (0.012 g, 0.054 mmol) was added and the reaction was heated to 100°C. After 18 hours, the reaction was partitioned with water (20 ml) and EtOAc (20 ml) and filtered. The filtrate was extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with brine (15 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using heptane and EtOAc as eluents to give tert-butyl N-[(1S)-1-{3-carbamoyl-5-[1-(difluoromethyl)-4. -nitro-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate (0.177 g, 72.4%) was obtained as a yellow oil. MS(ESI) m/z: 450.1 (MH) ⁺ .

^1H NMR (500MHz, CDCl ₃ ) δ 8.34 (s, 1H), 7.99 - 7.91 (m, 1H), 7.85 - 7.77 (m, 1H), 7.58 - 7.52 (m, 1H), 7.16 - 6.82 (m, 1H), 6.07 (br. s., 1H), 5.75 - 5.55 (m, 2H), 5.20 - 5.08 (m, 2H), 4.96 (br. s., 1H), 4.82 (br. s., 1H) , 2.62 - 2.46 (m, 2H), 1.40 (d, J=7.2 Hz, 9H).

84E. tert-Butyl N-[(1S)-1-{3-carbamoyl-5-[1-(difluoromethyl)-4-[(2R)-2-methylbut-3-enamido]- Preparation of 1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate

tert-Butyl N-[(1S)-1-{3-carbamoyl-5-[1-(difluoromethyl)-4- in acetone (40 ml)/water (12 ml) cooled to 0°C. nitro-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate (0.177 g, 0.392 mmol) was added to NH ₄ Cl (0.105 g, 1.960 mmol) and Zn (0.256 g, 3.92 mmol) was added. After 18 hours at room temperature, the reaction was filtered through paper and the filtrate was partitioned between water (20 ml) and EtOAc (25 ml). The aqueous layer was extracted with EtOAc (2 x 25 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO ₄ ), filtered and concentrated. (R)-2-methylbut-3-enoic acid (0.051 g, 0.510 mmol), pyridine (0.095 mL, 1.176 mmol) prepared as described in Intermediate 2 to a crude yellow oil in EtOAc (3 ml) at 0°C. and a 50% EtOAc solution of T3P® (0.233 mL, 0.784 mmol) were added. After 24 hours, the reaction was partitioned between saturated NaHCO ₃ (10 ml) and EtOAc (20 ml). The aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using hexane and EtOAc as eluents to give tert-butyl N-[(1S)-1-{3-carbamoyl-5-[1-(difluoromethyl)-4. -[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate (0.113 g, 57%) Obtained as a yellow oil. MS(ESI) m/z: 448.3 (M+Ht-butyl) ⁺ .

84F. tert-Butyl N-[(9R,10E,13S)-16-carbamoyl-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3. Preparation of 1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

tert-Butyl N-[(1S)-1-{3-carbamoyl-5-[1-(difluoromethyl)-4-[(2R)-2-methylbut in degassed DCE (11 ml) -3-enamido]-1H-pyrazol-5-yl]phenyl}but-3-en-1-yl]carbamate (0.113 g, 0.224 mmol) was added to a solution of the second generation Grubbs catalyst (0.08 g, 0.094 mmol) was added, and the resulting solution was heated in a microwave at 120° C. for 30 minutes. The reaction was purified directly by normal phase chromatography using DCM and 0-10% MeOH as eluent to give tert-butyl N-[(9R,10E,13S)-16-carbamoyl-3-(difluoromethyl). -9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaene -13-yl]carbamate (33 mg, 31%) was obtained as a tan solid. MS(ESI) m/z: 420.2 (M+Ht-butyl) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 7.95 (s, 1H), 7.82 - 7.78 (m, 2H), 7.10 (s, 1H), 5.73 (ddd, J=15.2, 10.5, 4.7 Hz, 1H), 4.65 (d, J=9.5 Hz, 1H), 4.54 (dd, J=15.2, 9.2 Hz, 1H), 3.19 - 3.09 (m, 1H), 2.70 (dt, J=12.1, 3.5 Hz, 1H), 2.03 (q, J=11.4 Hz, 1H), 1.46 (br. s., 9H), 1.08 (d, J=6.8 Hz, 3H).

84G. (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( Preparation of 18),2(6),4,14,16-pentaene-16-carboxamide

tert-Butyl N-[(9R,10E,13S)-16-carbamoyl-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3. 1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.033 g, 0.069 mmol) was added to PtO ₂ (5 mg) Hydrogenated in EtOH (1 ml) in the presence of . After 4 hours, the reaction was filtered through a 0.45 μM filter to yield 0.022 g of a tan solid. MS(ESI) m/z: 422.3 (M+Ht-butyl) ⁺ . The intermediate was deprotected in MeOH (1 ml) and 4 N HCl in dioxane (0.5 ml). After 3 hours, the reaction was concentrated. The residue was dissolved in DCM/MeOH, passed through a basic cartridge and concentrated to (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7- Triazatricyclo [12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaene-16-carboxamide (22 mg, 84%) was obtained as a brown solid. did. MS(ESI) m/z: 378.2(M+H) ⁺ .

84H. (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18 ), 2(6),4,14,16-pentaene-16-carboxamide production

6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol ( To 0.018 g, 0.058 mmol), and HATU (0.029 g, 0.076 mmol) was added DBU (0.013 mL, 0.087 mmol) in ACN (0.4 ml). After 30 minutes, (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octa Deca-1(18),2(6),4,14,16-pentaene-16-carboxamide (0.022g, 0.058 mmol) was added along with DMF (0.2 ml). After 18 hours, the reaction was diluted with DMF, filtered and purified by reverse phase HPLC with Phenomenex® Luna 5U 30x100 mm (10:90 ACN/H ₂ O in 90:10 ACN/H ₂ O, 0.1% TFA) (20 % B start, 14 min gradient) to give (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl ) phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[ 12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxamide (10 mg, 25%) was obtained as a white solid. MS(ESI) m/z: 668.3 (M+H) ⁺ .

^1H NMR (400MHz, CD ₃ OD) δ 8.36 (s, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.96 (s, 1H), 7.91 - 7.86 (m, 2H), 7.85 - 7.78 (m, 1H), 7.77 - 7.71 (m, 1H), 7.70 - 7.63 (m, 2H), 6.47 - 6.40 (m, 1H), 5.84 (dd, J=12.9, 3.4 Hz, 1H), 2.52 ( ddd, J=10.0, 6.7, 3.5 Hz, 1H), 2.47 - 2.38 (m, 1H), 2.21 - 2.11 (m, 1H), 1.98 - 1.86 (m, 1H), 1.67 - 1.47 (m, 2H), 1.22 (d, J=6.8 Hz, 1H), 1.16 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT = 7.39 min, purity = 98%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 18 nM.

Example 85

1-(4-chloro-2-{1-[(9R,13S)-3-( ^2H ₃ )methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl) -Preparation of 1H-1,2,3-triazole-4-carboxamide

85A. Preparation of 1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide

1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide (60 mg, TMSI (12 μL, 0.88 mmol) was added to the suspension (0.18 mmol). The solution was heated at 70°C for 3 hours. The reaction was cooled to room temperature and poured into 10% Na ₂ S ₂ O ₃ solution. The insoluble yellow solid formed was filtered, washed with water and the crude 1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-car Boxamide (30 mg, 41.8% yield) was obtained. MS(ESI) m/z: 317.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.57 (s, 1H), 8.02 (s, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.76 - 7.71 (m, 1H), 7.70 - 7.64 ( m, 1H), 6.39 (s, 1H).

85B. 1-(4-chloro-2-{1-[(9R,13S)-3-( ^2H ₃ )methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl) -Preparation of 1H-1,2,3-triazole-4-carboxamide

1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide (0.004 g, 0.013 mmol) in a small vial ) and HATU (6.24 mg, 0.016 mmol) were added DBU (2.86 μl, 0.019 mmol) in CH ₃ CN (0.8 ml). After 30 minutes, solid (9R,13S)-13-amino-3-( ^2H ₃ )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0, prepared as described in Intermediate 16. ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.038 g, 0.013 mmol) was added (rinsed with 0.2 ml DMF). The reaction was stirred for 18 hours, then diluted with DMF, filtered and concentrated. The residue was purified by preparative LCMS (5:95 ACN/H ₂ O to 95:5 ACN/H ₂ O, 10 mM NH ₄ OAc) to give 1-(4-chloro-2-{1- [(9R, _13S)-3-(2H3 ⁾ methyl-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18), 2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2,3-triazole- 4-Carboxamide (3.1 mg, 38% yield) was obtained as a white solid. MS(ESI) m/z: 601.08 (M+H) ⁺ .

¹ H NMR (500 MHz, CD ₃ OD) δ 8.47 - 8.41 (m, 1H), 8.03 (s, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.67 - 7.60 (m, 2H), 7.60 - 7.53 (m, 1H), 7.52 - 7.41 (m, 2H), 7.41 - 7.36 (m, 1H), 7.19 (d, J=7.4 Hz, 1H), 6.37 - 6.28 (m, 1H), 5.69 (d, J=9.6 Hz, 1H), 4.45 (br. s., 1H), 2.40 - 2.34 (m, 1H), 2.27 - 2.19 (m, 1H), 1.82 - 1.73 (m, 1H), 1.52 - 1.41 (m , 2H), 1.15 - 1.10 (m, 1H), 1.07 - 1.01 (m, 3H). Analytical HPLC (Method C) RT = 1.31 min, purity = 95%; Factor XIa Ki = 0.3 nM, plasma kallikrein Ki = 60 nM.

Example 86

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 Preparation of ,14,16-pentaen-8-one

86A. Preparation of 4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole

To a solution of 4-nitro-1H-pyrazole (5.1 g, 45.1 mmol) in THF (50 mL) at 0° C. was added N-cyclohexyl-N-methylcyclohexanamine (19.32 mL, 90 mmol), followed by SEM-Cl (12 mL, 67.7 mmol) was added dropwise. The reaction mixture was allowed to slowly warm to room temperature and stirred for 18 hours. The reaction mixture was concentrated and the residue was purified by normal phase chromatography using hexane and EtOAc as eluents to give 4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole (4.6 g, 43% yield) was obtained as a yellow oil. MS(ESI) m/z: 244 (MH) ⁺

^1H NMR (500MHz, CD ₃ Cl) δ 8.30 (s, 1H), 8.10 (s, 1H), 5.45 (s, 2H), 3.67 - 3.57 (m, 2H), 1.01 - 0.90 (m, 2H), 0.04 - 0.00 (m, 9H).

86B. tert-butyl N-[(1S)-1-[3-(4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)phenyl]but-3 -N-1-yl] Preparation of carbamate

To a solution of tert-butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (0.4 g, 1.226 mmol) in DMF (3.07 ml) was di( Adamantane-1-yl)(butyl)phosphine (0.066 g, 0.184 mmol), 4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole (0.298 g, 1.226 mmol), K ₂ CO ₃ (0.508 g, 3.68 mmol) and pivalic acid (0.043 ml, 0.368 mmol) were added. The reaction was purged with Ar for 10 minutes, then Pd(OAc) ₂ (0.028 g, 0.123 mmol) was added and the reaction was heated to 115° C. for 3 hours. The reaction mixture was diluted with EtOAc/water and filtered through paper to remove Pd. The filtrate was extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with water (15 ml), brine (15 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using hexane and EtOAc as eluents to give tert-butyl N-[(1S)-1-[3-(4-nitro-1-{[2-(trimethylsilyl)ethoxy. ]methyl}-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate (0.315 g, 53%) was obtained as a yellow oil. MS(ESI) m/z: 487.3 (MH) ⁺ .

^1H NMR (500MHz, CD ₃ Cl) δ 8.23 (s, 1H), 7.53 - 7.40 (m, 4H), 5.69 (ddt, J=17.1, 10.1, 7.2 Hz, 1H), 5.25 (s, 2H), 5.17 - 5.10 (m, 2H), 4.90 (br. s., 1H), 4.81 (br. s., 1H), 3.75 - 3.64 (m, 2H), 2.55 (br. s., 2H), 1.48 ( br. s., 9H), 0.96 - 0.88 (m, 2H), 0.07 - 0.02 (m, 9H).

86C. tert-Butyl N-[(1S)-1-[3-(4-amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)phenyl]but-3 -N-1-yl] Preparation of carbamate

tert-Butyl N-[(1S)-1-[3-(4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)phenyl]but-3 -en-1-yl]carbamate (0.315 g, 0.645 mmol) was dissolved in acetone (40 ml)/water (12 ml) and cooled to 0°C. NH ₄ Cl (0.172 g, 3.22 mmol) and Zn (0.421 g, 6.45 mmol) were added. The ice bath was removed. After 3 hours, the reaction was partitioned with water (20 ml) and EtOAc (75 ml) and filtered through paper. The aqueous layer was extracted with EtOAc (2 x 50 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using hexane and EtOAc as eluents to give tert-butyl N-[(1S)-1-[3-(4-amino-1-{[2-(trimethylsilyl)ethoxy ]methyl}-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate (0.269 g, 91%) was obtained as a yellow oil. MS(ESI) m/z: 459.5 (MH) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54 - 7.42 (m, 3H), 7.34 - 7.28 (m, 2H), 5.72 (ddt, J=17.0, 10.1, 7.0 Hz, 1H), 5.33 - 5.26 (m, 2H), 5.18 - 5.07 (m, 2H), 4.95 (br. s., 1H), 4.81 (br. s., 1H), 3.73 - 3.60 (m, 2H), 3.03 (br. s., 2H) , 2.63 - 2.52 (m, 2H), 1.50 - 1.36 (m, 9H), 0.97 - 0.88 (m, 2H), 0.04 -0.03 (m, 9H).

86D. tert-Butyl N-[(1S)-1-(3-{4-[(2R)-2-methylbut-3-enamido]-1-{[2-(trimethylsilyl)ethoxy]methyl} -1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]preparation of carbamate

tert-Butyl N-[(1S)-1-[3-(4-amino-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl in EtOAc (1 ml) )phenyl]but-3-en-1-yl]carbamate (0.269 g, 0.586 mmol) (R)-2-methylbut-3-enoic acid (0.076) prepared as described in Intermediate 2 in 1 mL EtOAc. g, 0.762 mmol) was added and the solution was cooled to 0°C. To the reaction mixture was added pyridine (0.142 ml, 1.759 mmol) and 50% EtOAc solution of T3P® (0.698 ml, 1.173 mmol). After 1 hour, the reaction was partitioned between saturated NaHCO ₃ (10 ml) and EtOAc (30 ml). The aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by normal phase chromatography using hexane and EtOAc as eluents to give tert-butyl N-[(1S)-1-(3-{4-[(2R)-2-methylbut-3-enami. [Figure]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamate (0.241 g, 76%) was obtained as a pink oil. MS(ESI) m/z: 541.6 (MH) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.18 (s, 1H), 7.53 - 7.41 (m, 2H), 7.41 - 7.35 (m, 2H), 7.18 (br. s., 1H), 5.92 (ddd, J =17.2, 10.1, 7.9 Hz, 1H), 5.81 - 5.65 (m, 1H), 5.37 - 5.30 (m, 2H), 5.25 - 5.10 (m, 4H), 4.93 (br. s., 1H), 4.82 - 4.73 (m, 1H), 3.75 - 3.66 (m, 2H), 3.12 (quin, J=7.2 Hz, 1H), 2.63 - 2.49 (m, 2H), 1.48 - 1.39 (m, 9H), 1.35 - 1.31 ( m, 3H), 1.00 - 0.90 (m, 2H), 0.03 - 0.02 (m, 9H).

86E. tert-Butyl N-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl) ethoxy]methyl}-3,4,7-triazatricyclo[12.3 Preparation of .1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

tert-Butyl N-[(1S)-1-(3-{4-[(2R)-2-methylbut-3-enamido]-1-{[2-(trimethylsilyl) in DCM (55 ml) ) A solution of ethoxy]methyl}-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamate (0.241 g, 0.446 mmol) was purged with Ar for 15 min. Second generation Grubbs catalyst (0.151 g, 0.178 mmol) was added and the reaction was heated to 40°C. After 24 hours, the reaction mixture was concentrated and the residue was purified by normal phase chromatography using DCM and 0-10% MeOH as eluents, then again using hexane and EtOAc as eluents to give tert-butyl N-[(9R ,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl) ethoxy]methyl}-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.224 g, 98%) was obtained as a dark solid. MS(ESI) m/z: 513.5 (M+H) ⁺ .

86F. tert-Butyl N-[(9R,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7-triazatricyclo[12.3.1.0 Preparation of ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

tert-Butyl N-[(9R,10E,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7-triazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.16 g, 0.312 mmol) was added to PtO ₂ (7.09 mg , 0.031 mmol) in EtOH (4 ml) at 55 psi. After 3 hours, the reaction was filtered through Celite® and concentrated to give tert-butyl N-[(9R,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl) ethoxy]methyl. }-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate ( 0.15 g, 93%) The desired product was obtained as a gray solid. MS(ESI) m/z: 515.5 (M+H) ⁺ .

86G. and 86H. (9R,13S)-13-amino-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one, and (9R,13S)-13-amino-9-methyl-3,4,7-triazatricyclo[ 12.3.1.0 Preparation of ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

tert-Butyl N-[(9R,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.15 g, 0.291 mmol) was dissolved in water (10 ml) in a microwave. Heated at 150°C for 30 minutes. Water was gently poured from the tarry material, lyophilized, and (9R,13S)-13-amino-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7-triaza. Tricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (MS(ESI) m/z: 415.5 (M+H) ⁺ )) and (9R,13S)-13-amino-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 A mixture of ,14,16-pentaen-8-one (MS(ESI) m/z: 285.5 (M+H) ⁺ ) (29 mg) was obtained, which was used 'as is' in the subsequent steps.

86I. (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 Preparation of ,14,16-pentaen-8-one

6-[3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidine prepared as described in Intermediate 10 in small vials. To -4-ol (0.015 g, 0.046 mmol), and HATU (0.023 g, 0.059 mmol) was added DBU (10.34 μl, 0.069 mmol) in CH ₃ CN (0.8 ml). After 30 min, (9R,13S)-13-amino-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7-triazatricyclo in DMF (0.8 ml) [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one and (9R,13S)-13-amino-9-methyl-3, Add a mixture of 4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,14,16-pentaen-8-one (13 mg) , the reaction was stirred for 24 hours. The reaction was diluted with DMF, filtered and purified by reverse phase HPLC on Phenomenex® Luna 5U 30x100 mm (10:90 MeOH/H ₂ O in 90:10 MeOH/H ₂ O, 0.1% TFA) (25% B starting, (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2- fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-8-one (2 mg, 7% yield) was obtained as a white solid. MS(ESI) m/z: 593.4 (M+H) ⁺ .

^1H NMR (400MHz, CD ₃ OD) δ 8.29 (s, 1H), 8.11 (s, 1H), 7.91 - 7.82 (m, 2H), 7.70 - 7.65 (m, 1H), 7.62 (s, 1H), 7.56 - 7.46 (m, 3H), 7.10 (d, J=7.5 Hz, 1H), 6.67 - 6.62 (m, 1H), 5.93 - 5.86 (m, 1H), 2.65 - 2.57 (m, 1H), 2.29 ( d, J=11.4 Hz, 1H), 2.11 (d, J=10.3 Hz, 1H), 1.98 (br. s., 1H), 1.65 (d, J=5.9 Hz, 1H), 1.59 - 1.50 (m, 1H), 1.40 (br. s., 1H), 1.15 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT = 7.38 min, purity = 90%; Factor XIa Ki = 1.8 nM, plasma kallikrein Ki = 90 nM.

Example 87

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of 2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) ,2(6),4,14,16-pentaen-8-one trifluoroacetate was prepared as described in Intermediate 7 in a manner similar to the procedure described in Example 56, 6-(3-chloro-2 -fluoro-6-(1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (0.034 g, 0.116 mmol), and (9R, prepared as described in Intermediate 30 13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), prepared using 4,14,16-pentaen-8-one (0.039 g, 0.116 mmol), (9R,13S)-13-{4-[3-chloro-2-fluoro-6 -(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate was obtained. MS(ESI) m/z: 610.2 [M+H] ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.57 (s, 1H), 8.43 (d, J=5.2 Hz, 1H), 7.87 (d, J=1.1 Hz, 1H), 7.53 (dd, J=8.5, 7.7 Hz, 1H), 7.50 - 7.41 (m, 3H), 7.39 - 7.32 (m, 2H), 7.25 - 7.18 (m, 3H), 6.22 (s, 1H), 5.75 - 5.65 (m, 1H), 2.43 - 2.35 (m, 1H), 2.01 - 1.91 (m, 1H), 1.76 - 1.64 (m, 8H), 1.32 - 1.22 (m, 1H), 1.21 - 1.10 (m, 1H), 0.67 (d, J= 7.2 Hz, 3H). Analytical HPLC (Method A): RT = 7.59 min, purity = 97.5%; Factor XIa Ki = 0.22 nM, plasma kallikrein Ki = 42 nM.

Example 88

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), Preparation of 2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), 2(6),4,14,16-pentaen-8-one trifluoroacetate was prepared as described in Intermediate 9 in a manner similar to the procedure described in Example 56, 6-(5-chloro-2- (4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (0.019 g, 0.062 mmol), and (9R,13S) prepared as described in Intermediate 30 -13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6) , prepared using 4,14,16-pentaen-8-one (0.021 g, 0.062 mmol), (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H -1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3, 4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate was obtained. . MS(ESI) m/z: 626.2 [M+H] ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.91 - 8.83 (m, 1H), 8.78 - 8.71 (m, 1H), 8.33 (s, 1H), 7.88 (d, J=2.5 Hz, 1H), 7.74 ( s, 2H), 7.69 - 7.67 (m, 1H), 7.65 (s, 1H), 7.63 (t, J=58 Hz, 1H), 7.52 - 7.50 (m, 1H), 6.36 (d, J=0.8 Hz) , 1H), 6.06 - 5.95 (m, 1H), 2.76 - 2.65 (m, 1H), 2.36 - 2.21 (m, 1H), 2.08 - 1.93 (m, 2H), 1.63 - 1.53 (m, 1H), 1.53 - 1.42 (m, 1H), 0.99 (d, J=6.9 Hz, 3H). Analytical HPLC (Method A): RT = 8.87 min, purity = 99.7%; Factor XIa Ki = 0.12 nM, plasma kallikrein Ki = 30 nM.

Example 89

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one; Preparation of trifluoroacetate

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate was prepared as described in Intermediate 10 in a manner similar to the procedure described in Example 56, 6-(3 -Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol (0.025 g, 0.063 mmol), and intermediate 30 (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca prepared as described. -Prepared using 1(18),2(6),4,14,16-pentaen-8-one (0.021 g, 0.063 mmol), (9R,13S)-13-{4-[3- chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}- 3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14, 16-pentaen-8-one trifluoroacetate was obtained. MS(ESI) m/z: 644.3 [M+H] ⁺ .

^1H NMR (400MHz, CD ₃ OD) δ 8.92 - 8.84 (m, 1H), 8.80 - 8.72 (m, 1H), 8.32 (s, 1H), 7.89 - 7.82 (m, 1H), 7.75 (s, 1H) ), 7.74 - 7.70 (m, 1H), 7.66 (t, J=58 Hz, 1H), 7.54 (d, J=1.5 Hz, 2H), 6.60 (s, 1H), 6.07 - 5.97 (m, 1H) , 2.76 - 2.65 (m, 1H), 2.36 - 2.23 (m, 1H), 2.09 - 1.96 (m, 2H), 1.65 - 1.42 (m, 2H), 1.00 (d, J=7.0 Hz, 3H). Analytical HPLC (Method A): RT = 8.36 min, purity = 98.8%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 11 nM.

Example 90

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca -Preparation of 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate was prepared as described in Intermediate 10 in a manner similar to the procedure described in Example 56, 6-( 3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol (0.054 g, 0.167 mmol), and intermediate 40 (9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] prepared as described in It was prepared using octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.055 g, 0.167 mmol). The crude product was purified by preparative HPLC to give (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2 -fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (45 mg, 34% yield) was obtained as a tan solid. did.

¹ H NMR (400MHz, CD ₃ OD) δ 8.82 (s, 1H), 8.75 (d, J=5.3 Hz, 1H), 8.36 - 8.32 (m, 1H), 7.87 (dd, J=8.6, 7.7 Hz, 1H), 7.81 (dd, J=5.1, 1.5 Hz, 1H), 7.73 (s, 1H), 7.61 - 7.53 (m, 2H), 6.00 (dd, J=12.7, 4.3 Hz, 1H), 4.51 - 4.33 (m, 1H), 4.13 - 3.86 (m, 2H), 3.39 - 3.35 (m, 2H), 2.71 (td, J=6.8, 3.1 Hz, 1H), 2.43 - 2.25 (m, 1H), 2.13 - 1.97 (m, 1H), 1.68 - 1.40 (m, 2H), 1.03 (d, J=6.8 Hz, 6H), 0.75 (br. s., 1H). MS(ESI) m/z: 638.5 [M+H] ⁺ . Analytical HPLC (Method A): RT = 7.32 min, purity = >95.0%; Factor XIa Ki = 0.34 nM, plasma kallikrein Ki = 28 nM.

Example 91

(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca -Preparation of 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate was prepared as described in Intermediate 16 in a manner similar to the procedure described in Example 56, 6-( 5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (0.049 g, 0.152 mmol), and intermediate 40 (9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] prepared as described in It was prepared using octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.050 g, 0.152 mmol). The crude product was purified by preparative HPLC to give (9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazole-1 -yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (32 mg, 27% yield) was obtained as a white solid. did.

¹ H NMR (400MHz, CD ₃ OD) δ 8.75 (s, 1H), 8.69 (d, J=5.1 Hz, 1H), 8.56 - 8.50 (m, 1H), 7.87 (d, J=2.4 Hz, 1H) , 7.79 - 7.61 (m, 4H), 7.55 (s, 1H), 7.16 - 6.80 (m, 1H), 6.34 (d, J=0.4 Hz, 1H), 5.95 (dd, J=12.7, 4.1 Hz, 1H) ), 4.47 - 4.28 (m, 2H), 4.09 - 3.87 (m, 2H), 2.67 (td, J=6.8, 3.0 Hz, 1H), 2.34 - 2.19 (m, 1H), 2.09 - 1.91 (m, 2H) ), 1.65 - 1.34 (m, 2H), 1.00 (d, J=6.8 Hz, 3H), 0.70 (br. s., 1H). MS(ESI) m/z: 636.5 [M+H] ⁺ . Analytical HPLC (Method A): RT = 7.32 min, purity = >95.0%; Factor XIa Ki = 2.8 nM, plasma kallikrein Ki = 220 nM.

Example 92

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of 2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) ,2(6),4,14,16-pentaen-8-one trifluoroacetate was prepared as described in Intermediate 9 in a manner similar to the procedure described in Example 56, 6-(5-chloro-2 -(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (0.042 g, 0.137 mmol), and (9R,13S prepared as described in Intermediate 40 )-13-Amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), 4,14,16-pentaen-8-one (0.045 g, 0.137 mmol) was used to prepare it. The crude product was purified by preparative HPLC to (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl] -6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (65 mg, 61% yield) was obtained as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ 8.79 (s, 1H), 8.73 (d, J=5.1 Hz, 1H), 8.40 - 8.30 (m, 1H), 7.88 (d, J=2.2 Hz, 1H) , 7.81 (dd, J=5.1, 1.5 Hz, 1H), 7.76 - 7.70 (m, 2H), 7.67 - 7.61 (m, 1H), 7.58 (s, 1H), 6.37 (d, J=0.4 Hz, 1H) ), 5.96 (dd, J=12.5, 4.2 Hz, 1H), 4.46 - 4.33 (m, 2H), 4.09 - 3.91 (m, 3H), 3.35 (s, 1H), 2.69 (td, J=6.8, 3.0 Hz, 1H), 2.39 - 2.24 (m, 1H), 2.12 - 1.94 (m, 2H), 1.66 - 1.40 (m, 2H), 1.02 (d, J=7.0 Hz, 3H), 0.73 (br. s. , 1H). MS(ESI) m/z: 620.5 [M+H] ⁺ . Analytical HPLC (Method A): RT = 7.29 min, purity = >95.0%; Factor XIa Ki = 1.3 nM, plasma kallikrein Ki = 130 nM.

Example 93

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2 (6), Preparation of 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2 (6),4,14,16-pentaen-8-one trifluoroacetate was prepared as described in Intermediate 20 in a manner similar to the procedure described in Example 56, 6-(5-chloro-2-( 1H-tetrazol-1-yl)phenyl)pyrimidin-4-ol (0.037 g, 0.137 mmol), and (9R,13S)-13-amino-3-(2-hydride prepared as described in Intermediate 40 Roxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene- Prepared using 8-one (0.045 g, 0.137 mmol). The crude product was purified by preparative HPLC to obtain (9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6 -Oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]Octadeca-1(18),2(6),4,14,16-pentaen-8-one (52 mg, 52% yield) was obtained as a light white solid.

¹ H NMR (400MHz, CD ₃ OD) δ 9.42 (s, 1H), 8.68 (d, J=5.1 Hz, 2H), 7.88 (d, J=2.2 Hz, 1H), 7.78 - 7.72 (m, 2H) , 7.67 (d, J=8.4 Hz, 2H), 7.55 (s, 1H), 6.49 (s, 1H), 5.93 (d, J=8.8 Hz, 1H), 4.45 - 4.29 (m, 2H), 4.08 - 3.88 (m, 3H), 3.32 (s, 1H), 2.66 (d, J=7.0 Hz, 1H), 2.24 (t, J=13.0 Hz, 1H), 2.08 - 1.88 (m, 2H), 1.65 - 1.49 (m, 1H), 1.41 (br. s., 1H), 0.98 (d, J=6.8 Hz, 3H), 0.67 (br. s., 1H). MS(ESI) m/z: 587.5 [M+H] ⁺ . Analytical HPLC (Method A): RT = 6.40 min, purity = >95.0%; Factor XIa Ki = 0.65 nM, plasma kallikrein Ki = 45 nM.

Example 94

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca -Preparation of 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate was prepared as described in Intermediate 15 in a manner analogous to the procedure described in Example 56. 5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (47 mg, 0.137 mmol), and Intermediate 40 (9R,13S)-13-amino-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] prepared as described in It was prepared using octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.045 g, 0.137 mmol). The crude product was purified by preparative HPLC to give (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1 -yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (67 mg, 61% yield) was obtained as a white solid.

^1H NMR (400MHz, CD ₃ OD) δ 8.79 (s, 1H), 8.72 (s, 1H), 8.68 - 8.61 (m, 1H), 7.88 - 7.82 (m, 1H), 7.78 - 7.69 (m, 2H) ), 7.68 - 7.61 (m, 2H), 7.54 (s, 1H), 6.40 (s, 1H), 5.93 (dd, J=12.7, 4.1 Hz, 1H), 4.42 - 4.27 (m, 2H), 4.03 - 3.86 (m, 2H), 2.65 (dt, J=6.8, 3.3 Hz, 1H), 2.33 - 2.15 (m, 1H), 2.07 - 1.87 (m, 2H), 1.64 - 1.48 (m, 1H), 1.41 ( td, J=10.0, 5.2 Hz, 1H), 1.01 - 0.93 (m, 3H), 0.66 (br. s., 1H). MS(ESI) m/z: 654.5 [M+H] ⁺ . Analytical HPLC (Method A): RT = 8.10 min, purity = >95.0%; Factor XIa Ki = 1.1 nM, plasma kallikrein Ki = 130 nM.

Example 95

2-[(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6 -Oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( Preparation of 18),2(6),4,14,16-pentaen-3-yl]acetic acid trifluoroacetate

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazole-1 prepared as described in Example 90 in acetone (2 mL) -yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15 -tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (0.034 g, 0.053 mmol) The solution was cooled to 0°C. A 2.86 M solution of Jones reagent (0.037 mL, 0.107 mmol) was then added to this cooled mixture and the resulting reaction mixture was allowed to warm to room temperature over a period of 2 hours. The reaction mixture was then quenched with 0.5 mL of IPA and concentrated. The resulting residue was purified by preparative HPLC purification to obtain 2-[(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazole- 1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic acid trifluoroacetate (8 mg, 19% yield) as a white solid. It was obtained as.

¹ H NMR (400MHz, CD ₃ OD) δ 8.85 (s, 1H), 8.74 (d, J=5.1 Hz, 1H), 8.34 (s, 1H), 7.87 (dd, J=8.6, 7.5 Hz, 1H) , 7.72 (s, 1H), 7.61 - 7.53 (m, 2H), 7.49 (dd, J=5.1, 1.5 Hz, 1H), 6.62 (s, 1H), 6.04 (dd, J=12.3, 4.2 Hz, 1H) ), 5.27 - 5.06 (m, 2H), 2.72 (dt, J=6.7, 3.4 Hz, 1H), 2.30 (t, J=12.7 Hz, 1H), 2.15 - 1.97 (m, 2H), 1.69 - 1.41 ( m, 2H), 1.03 (d, J=7.0 Hz, 3H), 0.71 (br. s., 1H). MS(ESI) m/z: 652.2 [M+H] ⁺ . Analytical HPLC (Method A): RT = 7.45 min, purity = >95.0%; Factor XIa Ki = 0.11 nM, plasma kallikrein Ki = 12 nM.

Example 96

2-[(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6 -Oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( Preparation of 18),2(6),4,14,16-pentaen-3-yl]acetic acid trifluoroacetate

2-[(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6 -Oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-3-yl]acetic acid was prepared as (9R,13S)-13, prepared as described in Example 91, in a manner similar to the procedure described in Example 95. -(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyri midin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2 (6), 4,14,16-pentaen-8-one prepared using trifluoroacetate (0.024 g, 0.038 mmol), 2-[(9R,13S)-13-(4-{5- Chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)- 9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene- 3-yl]acetic acid trifluoroacetate (6 mg, 20% yield) was obtained as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ 8.83 (s, 1H), 8.72 (d, J=5.1 Hz, 1H), 8.56 (s, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.72 - 7.66 (m, 2H), 7.59 (s, 1H), 7.49 (dd, J=5.1, 1.3 Hz, 1H), 7.19 - 6.86 (m, 1H), 6.38 (s) , 1H), 6.03 (dd, J=12.7, 4.3 Hz, 1H), 5.27 - 5.06 (m, 2H), 2.72 (dt, J=6.6, 3.3 Hz, 1H), 2.34 - 2.22 (m, 1H), 2.13 - 1.94 (m, 2H), 1.68 - 1.40 (m, 2H), 1.03 (d, J=7.0 Hz, 3H), 0.71 (br. s., 1H). MS(ESI) m/z: 650.3 [M+H] ⁺ . Analytical HPLC (Method A): RT = 7.52 min, purity = >95.0%; Factor XIa Ki = 0.65 nM, plasma kallikrein Ki = 78 nM.

Example 97

2-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1, 6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2( 6), 4,14,16-pentaen-3-yl] Preparation of acetic acid trifluoroacetate

2-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1, 6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2( 6),4,14,16-pentaen-3-yl]acetic acid trifluoroacetate was prepared as described in Example 92, in a manner similar to the procedure described in Example 95, (9R,13S)-13- {4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl} -3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, Prepared using 14,16-pentaen-8-one trifluoroacetate (0.038 g, 0.061 mmol), 2-[(9R,13S)-13-{4-[5-chloro-2-(4 -chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4 ,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic acid trifluoroacetate (8 mg, 17% yield) was obtained as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ 8.85 (s, 1H), 8.73 (d, J=5.1 Hz, 1H), 8.36 (s, 1H), 7.92 - 7.88 (m, 1H), 7.79 - 7.64 ( m, 3H), 7.59 (s, 1H), 7.49 (dd, J=5.1, 1.3 Hz, 1H), 6.38 (s, 1H), 6.03 (dd, J=12.5, 4.0 Hz, 1H), 5.27 - 5.04 (m, 2H), 2.72 (m, 1H), 2.30 (m, 1H), 2.14 - 1.97 (m, 2H), 1.69 - 1.42 (m, 2H), 1.03 (d, J=6.8 Hz, 3H), 0.71 (br. s., 1H). MS(ESI) m/z: 634.3 [M+H] ⁺ . Analytical HPLC (Method A): RT = 7.49 min, purity = >95.0%; Factor XIa Ki = 0.38 nM, plasma kallikrein Ki = 52 nM.

Example 98

2-[(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6) ,4,14,16-pentaen-3-yl]Manufacture of acetic acid trifluoroacetate

2-[(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ,4,14,16-pentaen-3-yl]acetic acid trifluoroacetate was prepared as described in Example 93, in a manner similar to the procedure described in Example 95, as (9R,13S)-13-{4 -[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-( 2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16- Prepared using pentaen-8-one trifluoroacetate (0.020 g, 0.034 mmol), 2-[(9R,13S)-13-{4-[5-chloro-2-(1H-1,2 ,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetra Azatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]acetic acid trifluoroacetate (5.1 mg, 20% yield) was obtained as a white solid.

^1H NMR (400MHz, CD ₃ OD) δ 9.45 (s, 1H), 8.80 - 8.68 (m, 2H), 7.95 - 7.90 (m, 1H), 7.83 - 7.76 (m, 1H), 7.74 - 7.67 (m , 2H), 7.59 (s, 1H), 7.49 (dd, J=5.1, 1.3 Hz, 1H), 6.53 (s, 1H), 6.01 (dd, J=12.5, 4.0 Hz, 1H), 5.28 - 5.05 ( m, 2H), 2.71 (m, 1H), 2.27 (m, 1H), 2.13 - 1.95 (m, 2H), 1.66 - 1.39 (m, 2H), 1.03 (d, J=7.0 Hz, 3H), 0.72 (br. s., 1H). MS(ESI) m/z: 601.3 [M+H] ⁺ . Analytical HPLC (Method A): RT = 6.62 min, purity = >95.0%; Factor XIa Ki = 0.16 nM, plasma kallikrein Ki = 20 nM.

Example 99

2-[(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6 -Oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( Preparation of 18),2(6),4,14,16-pentaen-3-yl]acetic acid trifluoroacetate

2-[(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6 -Oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-3-yl]acetic acid trifluoroacetate was prepared as described in Example 94 (9R, 13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6 -dihydropyrimidin-1-yl)-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( Prepared using 18),2(6),4,14,16-pentaen-8-one trifluoroacetate (0.038 g, 0.058 mmol), 2-[(9R,13S)-13-(4 -{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidine-1 -yl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16 -pentaen-3-yl]acetic acid trifluoroacetate (7.5 mg, 16% yield) was obtained as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ 8.84 (s, 1H), 8.80 (s, 1H), 8.73 - 8.68 (m, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.80 - 7.75 ( m, 1H), 7.71 (m, 2H), 7.58 (s, 1H), 7.49 (dd, J=5.1, 1.3 Hz, 1H), 6.46 (s, 1H), 6.03 (dd, J=12.4, 4.1 Hz) , 1H), 5.26 - 5.06 (m, 2H), 2.77 - 2.66 (m, 1H), 2.27 (m, 1H), 2.13 - 1.94 (m, 2H), 1.67 - 1.40 (m, 2H), 1.02 (d) , J=6.8 Hz, 3H), 0.71 (br. s., 1H). MS(ESI) m/z: 668.3 [M+H]+; Factor XIa Ki = 0.29 nM, plasma kallikrein Ki = 52 nM.

Example 100

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) , Preparation of 4,14,16-pentaen-8-one trifluoroacetate

100A. (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy] methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0 Preparation of ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one was prepared as described in Intermediate 10 in a manner similar to the procedure described in Example 56. -(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol (0.027 g, 0.083 mmol), and Benzyl N-[(9R,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15- prepared as described in Intermediate 41 Tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.034 g, 0.081 mmol) was used. Prepared by (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]- 6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (10 mg, 14% yield) was obtained as a light white solid. MS(ESI) m/z: 723.5 [M+H] ⁺ .

100B. (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) , Preparation of 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl in DCM (0.8 mL) ]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraaza To a solution of tricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (10 mg, 0.014 mmol) was added TFA (0.2 mL, 2.60 mmol) was added, and the resulting solution was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated and the residue was purified by preparative HPLC purification to (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3- triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[ 12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (4.8 mg, 46% yield) was obtained as a light pink solid. did.

¹ H NMR (400MHz, CD ₃ OD) δ 8.74 - 8.59 (m, 2H), 8.42 - 8.30 (m, 1H), 7.99 (s, 1H), 7.88 (dd, J=8.6, 7.7 Hz, 1H), 7.77 (s, 1H), 7.67 (dd, J=5.3, 1.3 Hz, 1H), 7.58 (dd, J=8.6, 1.5 Hz, 1H), 6.65 (s, 1H), 6.07 (d, J=8.4 Hz) , 1H), 2.90 - 2.74 (m, 1H), 2.44 - 2.18 (m, 2H), 2.14 - 2.02 (m, 1H), 1.83 - 1.67 (m, 1H), 1.63 - 1.47 (m, 1H), 1.11 (d, J=6.8 Hz, 3H), 1.00 (br. s., 1H). MS(ESI) m/z: 594.5 [M+H] ⁺ . Analytical HPLC (Method A): RT = 7.11 min, purity = >95.0%; Factor XIa Ki = 1.6 nM, plasma kallikrein Ki = 85 nM.

Example 101

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14, Preparation of 16-pentaen-8-one trifluoroacetate

101A. (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,14,16-pentaen-8-one was prepared as described in Intermediate 9, in a manner similar to the procedure described in Example 56, using 6-(5-chloro -2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (0.034 g, 0.110 mmol), and benzyl N prepared as described in Intermediate 41 -[(9R,13S)-9-methyl-8-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]Octadeca-1(18),2(6),4,14,16-pentaen-13-yl]prepared using carbamate (0.046 g, 0.110 mmol), (9R,13S)- 13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-9-methyl-3-{[2-(trimethylsilyl) ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18) ,2(6),4,14,16-pentaen-8-one (12 mg, 14% yield) was obtained as a light yellow solid. MS(ESI) m/z: 706.5 [M+H] ⁺ .

101B. (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14, Preparation of 16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo in DCM (0.8 mL) -1,6-dihydropyrimidin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3. TFA (0.2 mL, 2.60 mmol) was added to a solution of 1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (12 mg, 0.017 mmol). And the reaction was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated and the residue was purified by preparative HPLC purification to (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3- triazol-1-yl) phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (5.3 mg, 43% yield) was obtained as a light pink solid.

¹ H NMR (400MHz, CD ₃ OD) δ 8.72 - 8.57 (m, 2H), 8.37 (s, 1H), 7.99 (s, 1H), 7.91 (d, J=2.2 Hz, 1H), 7.82 - 7.72 ( m, 2H), 7.70 - 7.63 (m, 2H), 6.41 (s, 1H), 6.11 - 5.95 (m, 1H), 2.81 (td, J=6.8, 3.4 Hz, 1H), 2.44 - 2.17 (m, 2H), 2.15 - 2.01 (m, 1H), 1.80 - 1.65 (m, 1H), 1.62 - 1.46 (m, 1H), 1.11 (d, J=7.0 Hz, 3H), 1.01 (br. s., 1H) ). MS(ESI) m/z: 576.4 [M+H] ⁺ . Analytical HPLC (Method A): RT = 6.98 min, purity = >95.0%; Factor XIa Ki = 4.2 nM, plasma kallikrein Ki = 300 nM.

Example 102

Methyl (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),3,5, Preparation of 14,16-pentaene-4-carboxylate trifluoroacetate

102A. Preparation of (S)-tert-butyl (1-(4-hydrazinylpyridin-2-yl)but-3-en-1-yl) carbamate

A vial equipped with a Teflon septum stopper was prepared with (S)-tert-butyl (1-(4-chloropyridin-2-yl)but-3-en-1- prepared as described in Intermediate 23 in EtOH (10 mL). 1) carbamate (2 g, 7.0 mmol), and 35% aqueous hydrazine (10 mL, 111 mmol, 15.75 equiv). The solution was heated at 115° C. for 18 hours by means of an aluminum block. The reaction was concentrated to give a pink oil. The residue was purified by normal phase silica gel chromatography to obtain (S)-tert-butyl (1-(4-hydrazinylpyridin-2-yl)but-3-en-1-yl)carbamate (1.67 g, 85% yield) was obtained as a yellow foam.

^1H NMR (400MHz, CDCl ₃ ) δ 8.22 (d, J=5.7 Hz, 1H), 6.60 (s, 1H), 6.57 (dd, J=5.5, 2.4 Hz, 1H), 5.79 - 5.54 (m, 3H) ), 5.14 - 4.99 (m, 2H), 4.74 - 4.62 (m, 1H), 2.59 (t, J=6.7 Hz, 2H), 1.52 - 1.40 (m, 9H). MS(ESI) m/z: 279.2 (M+H) ⁺ .

102B. (S)-Ethyl 5-amino-1-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)-1H-pyrazole- Preparation of 3-carboxylates

Sodium (Z)-1-cyano-3-ethoxy-3-oxoprop-1-en-2-oleate (0.29 g, 1.8 mmol) was dissolved in (S)-tert-butyl in EtOH (15 ml). (1-(4-hydrazinylpyridin-2-yl)but-3-en-1-yl)carbamate (0.50 g, 1.8 mmol). TFA (0.4 ml, 5.39 mmol, 3 equiv) was added dropwise and the solid was slowly dissolved upon heating to 80°C. Stirring was continued at 80°C for 2 hours and then the reaction was cooled to room temperature. The reaction was concentrated to an oil and the residue was dissolved in EtOAc. The organic layer was washed with pH = 7 phosphate buffer, separated and the organic layer was concentrated to give an oil. The crude oil was purified by normal phase silica gel chromatography to obtain (S)-ethyl 5-amino-1-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl) Pyridin-4-yl)-1H-pyrazole-3-carboxylate (0.7 g, 97% yield) was obtained as a clear, colorless, thick oil.

¹ H NMR (400MHz, CDCl ₃ ) δ 8.71 - 8.67 (m, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.60 (dd, J=5.4, 2.1 Hz, 1H), 6.20 (s, 1H) ), 5.79 - 5.66 (m, 1H), 5.56 - 5.42 (m, 1H), 5.15 - 5.06 (m, 3H), 4.93 - 4.82 (m, 1H), 4.44 (q, J=7.1 Hz, 2H), 4.03 (br. s., 2H), 2.66 (m, 2H), 1.46 (s, 9H), 1.45 - 1.41 (t, J=7.1 Hz, 3H). MS(ESI) m/z: 402.2 (M+H) ⁺ .

102C. Ethyl 1-(2-((S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)-5-((R)-2- Preparation of methylbut-3-enamido)-1H-pyrazole-3-carboxylate

Solution ( _S )-ethyl 5-amino-1-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl) in 3-neck 250 mL RBF, flushed with N 2 Pyridin-4-yl)-1H-pyrazole-3-carboxylate (1.75 g, 4.36 mmol) and EtOAc (15 mL) were added. The solution was cooled to -10°C and (R)-2-methylbut-3-enoic acid (436 mg, 4.36 mmol), pyridine (0.705 mL, 8.72 mmol) and T3P® (3.89 mL) as prepared in Intermediate 2. , 6.54 mmol) was added. The cooling bath was removed and the solution was allowed to warm to room temperature and stirred for 20 hours. Water (20 mL) and EtOAc (20 mL) were added and the mixture was stirred for 30 minutes. The organic phase was separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated. Purification by normal phase chromatography eluting with gradient DCM/MeOH gave ethyl 1-(2-((S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridine- 4-yl)-5-((R)-2-methylbut-3-enamido)-1H-pyrazole-3-carboxylate (1.81 g, 86% yield) was obtained as a white foamy solid. MS(ESI) m/z: 484.5 [M+H] ⁺ .

102D. Ethyl (10E,13S)-13-{[(tert-butoxy)carbonyl]amino}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]Preparation of octadeca-1(18),3,5,10,14,16-hexaene-4-carboxylate

Ethyl 1-(2-((S)-1-((tert-butoxycarbonyl)amino)but-3-ene-1- in DCM (30 mL) in 250 mL, 3 _- neck RBF, N 2 flushed. 1) pyridin-4-yl)-5-((R)-2-methylbut-3-enamido)-1H-pyrazole-3-carboxylate (1.81 g, 3.74 mmol) and CH ₃ SO ₃ A solution of H (0.23 ml, 3.56 mmol) was added. The resulting solution was heated to 40°C. The solution was aerated with Ar for 15 minutes. Second generation Grubbs catalyst (253 mg, 0.298 mmol) dissolved in DCM (10 mL) was added dropwise over a period of 10 minutes at 40°C. The reaction mixture was heated at 40° C. overnight. After cooling to room temperature, the solvent was removed and the residue was purified by normal phase chromatography eluting with a gradient of DCM/MeOH to give ethyl (10E,13S)-13-{[(tert-butoxy)carbonyl]amino. }-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),3,5,10,14,16-hexaene -4-Carboxylate (670 mg, 39% yield) was obtained as a gray solid. MS(ESI) m/z: 556.5 [M+H] ⁺ .

102E. Ethyl (13S)-13-{[(tert-butoxy)carbonyl]amino}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),3,5,14,16-pentaene-4-carboxylate

Pd/C (0.16 g, 0.147 mmol) was dissolved in ethyl (10E,13S)-13-{[(tert-butoxy)carbonyl]amino}-9-methyl-8-oxo-2, 3,7,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),3,5,10,14,16-hexaene-4-carboxylate (670 mg, 1.471 mmol ) was added to a 250 mL Parr hydrogenation flask containing a solution of The flask was purged with N ₂ , pressurized with 55 psi of H ₂ and allowed to stir overnight. The reaction was filtered through a pad of Celite® and concentrated to ethyl (13S)-13-{[(tert-butoxy)carbonyl]amino}-9-methyl-8-oxo-2,3,7,15. -Tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate (500 mg, 70% yield) was obtained as a yellow-brown solid. did. MS(ESI) m/z: 458.4 [M+H] ⁺ .

102F. Ethyl (9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),3,5 ,14,16-pentaene-4-carboxylate, bis hydrochloride

Ethyl (13S)-13-{[(tert-butoxy)carbonyl]amino}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3. A solution of 1.0 ^2,6 ]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate (500 mg, 1.093 mmol) in 4 M HCl in dioxane (5 mL, 20.0 mmol) was added, and the resulting solution was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to give ethyl (9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18),3,5,14,16-pentaene-4-carboxylate, bis hydrochloride (380 mg, 97% yield, mixture of methyl and ethyl esters) was obtained as a light yellow solid. Additionally, methyl (9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraaza due to transesterification of ethyl ester to methyl ester because MeOH was used as solvent. The formation of tricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate, bis hydrochloride was observed. Ethyl (9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),3,5 ,14,16-pentaene-4-carboxylate, bis hydrochloride and methyl (9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[ 12.3.1.0 ^2,6 ] A mixture of octadeca-1(18),3,5,14,16-pentaene-4-carboxylate and bis hydrochloride was dissolved in MeOH (4 mL) to give a clear light brown solution. Obtained. The solution was added to a pre-rinsed Agilent® Stratosphere SPE PL-HCO ₃ MP resin cartridge. Gravity filtration eluting with MeOH gave a clear, slightly yellow filtrate. Concentrate to give ethyl (9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),3 ,5,14,16-pentaene-4-carboxylate (MS(ESI) m/z: 330.5 [M+H] ⁺ ) and methyl (9R,13S)-13-amino-9-methyl-8- Oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate (295 mg, 97%) carboxylate (MS(ESI) m/z: 344.3 [M+H] ⁺ ) mixture was obtained as a light brown solid.

102G. Methyl (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),3,5, Preparation of 14,16-pentaene-4-carboxylate trifluoroacetate

Methyl (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),3,5, 14,16-pentaene-4-carboxylate trifluoroacetate was prepared as described in Intermediate 9 in a manner similar to the procedure described in Example 56, 6-(5-chloro-2-(4-chloro- 1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (0.035 g, 0.115 mmol), and ethyl (9R,13S)-13-amino-9-methyl-8-oxo -2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate and methyl (9R, 13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),3,5,14,16 Prepared using a mixture of -pentaene-4-carboxylates (0.041 g, 0.115 mmol), methyl (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H- 1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15- tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate and ethyl (9R,13S)-13-{4-[ 5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl -8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate A mixture was obtained, which was further purified by preparative HPLC to give the desired methyl (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazole -1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate trifluoroacetate (7 mg, 8% yield) was obtained as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ 8.95 (s, 1H), 8.74 (d, J=5.3 Hz, 1H), 8.34 (s, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.68 - 7.58 (m, 2H), 6.84 (s, 1H), 6.37 (s, 1H), 6.12 (dd, J=12.4 , 5.0 Hz, 1H), 3.94 (s, 3H), 2.84 (br. s., 1H), 2.34 - 2.12 (m, 2H), 2.08 - 1.92 (m, 1H), 1.80 - 1.48 (m, 2H) , 0.98 (d, J=6.8 Hz, 3H), 0.45 (br. s., 1H). MS(ESI) m/z: 634.3 [M+H] ⁺ . Analytical HPLC (Method A): RT = 9.07 min, purity = >95.0%; Factor XIa Ki = 11 nM, plasma kallikrein Ki = 360 nM.

Example 103

Methyl (9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo -1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ] octadeca-1 (18) ,3,5,14,16-pentaene-4-carboxylate trifluoroacetate production

Methyl (9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo -1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ] octadeca-1 (18) ,3,5,14,16-pentaene-4-carboxylate trifluoroacetate was reacted with 6-(5-chloro-2-) prepared as described in Intermediate 16 in a manner similar to the procedure described in Example 56. (4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (0.037 g, 0.115 mmol), and prepared as described in Example 102F ethyl (9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),3, 5,14,16-pentaene-4-carboxylate and methyl (9R,13S)-13-amino-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 Prepared using a mixture of ^2,6 ]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate (0.041 g, 0.115 mmol), methyl (9R,13S)- 13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydro Pyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),3,5,14, 16-pentaene-4-carboxylate and ethyl (9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazole -1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 A mixture of ^2,6 ]octadeca-1(18),3,5,14,16-pentaene-4-carboxylates was obtained, which was further purified by preparative HPLC to give methyl (9R,13S) -13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-di Hydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),3,5,14 ,16-pentaene-4-carboxylate trifluoroacetate (7 mg, 8% yield) was obtained as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ 8.95 (s, 1H), 8.75 (d, J=5.3 Hz, 1H), 8.59 - 8.55 (m, 1H), 7.93 (d, J=2.4 Hz, 1H) , 7.84 (d, J=2.0 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.73 - 7.68 (m, 1H), 7.64 (dd, J=5.5, 2.0 Hz, 1H), 7.19 - 6.88 (m , 1H), 6.86 (s, 1H), 6.39 (s, 1H), 6.14 (dd, J=12.5, 5.1 Hz, 1H), 3.97 (s, 3H), 2.85 (d, J=6.8 Hz, 1H) , 2.36 - 2.13 (m, 2H), 2.08 - 1.92 (m, 1H), 1.77 - 1.51 (m, 2H), 1.01 (d, J=6.8 Hz, 3H), 0.45 (d, J=13.6 Hz, 1H) ). MS(ESI) m/z: 650.3 [M+H] ⁺ . Analytical HPLC (Method A): RT = 8.98 min, purity = >95.0%; Factor XIa Ki = 6.5 nM, plasma kallikrein Ki = 200 nM.

Example 104

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),3,5,14 , Production of 16-pentaene-4-carboxylic acid trifluoroacetate

Ethyl (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl] prepared as described in Example 102 -6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca- 1(18),3,5,14,16-pentaene-4-carboxylate (0.035 g, 0.054 mmol) was hydrolyzed using 2 M LiOH solution (0.08 mL, 0.162 mmol) at room temperature for 1 h. did. The reaction was neutralized using 1 N HCl and concentrated. The crude product was purified using preparative HPLC to obtain (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl ]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca -1(18),3,5,14,16-pentaene-4-carboxylic acid trifluoroacetate (20 mg, 48% yield) was obtained as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ 8.98 (s, 1H), 8.76 (d, J=5.3 Hz, 1H), 8.36 (s, 1H), 7.92 (d, J=2.2 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.79 - 7.73 (m, 1H), 7.70 - 7.63 (m, 2H), 6.85 (s, 1H), 6.40 (d, J=0.7 Hz, 1H), 6.15 ( dd, J=12.4, 5.0 Hz, 1H), 2.88 (d, J=8.8 Hz, 1H), 2.38 - 2.15 (m, 2H), 2.10 - 1.94 (m, 1H), 1.80 - 1.52 (m, 2H) , 1.01 (d, J=6.8 Hz, 3H), 0.48 (br. s., 1H). MS(ESI) m/z: 620.3 [M+H] ⁺ . Analytical HPLC (Method A): RT = 7.96 min, purity = >95.0%; Factor XIa Ki = 1.7 nM, plasma kallikrein Ki = 470 nM.

Example 105

(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ] octadeca-1 (18), Preparation of 3,5,14,16-pentaene-4-carboxylic acid trifluoroacetate

Ethyl (9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazole-1 prepared as described in Example 103 -yl] phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo [12.3.1.0 ^{2, 6} ]octadeca-1(18),3,5,14,16-pentaene-4-carboxylate (0.035 g, 0.053 mmol) was dissolved in 1 at room temperature using 2 M LiOH (0.079 mL, 0.158 mmol). Hydrolyzed over time. The reaction was neutralized using 1 N HCl and concentrated. The crude product was purified using preparative HPLC purification to obtain (9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazole. -1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-8-oxo-2,3,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),3,5,14,16-pentaene-4-carboxylic acid trifluoroacetate (10 mg, 24% yield) was obtained as a white solid.

¹ H NMR (400MHz, CD ₃ OD) δ 8.96 (s, 1H), 8.75 (d, J=5.3 Hz, 1H), 8.60 - 8.55 (m, 1H), 7.93 (d, J=2.2 Hz, 1H) , 7.85 (d, J=1.8 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.73 - 7.62 (m, 2H), 7.20 - 6.89 (m, 1H), 6.85 (s, 1H), 6.39 (s , 1H), 6.15 (dd, J=12.5, 4.8 Hz, 1H), 2.93 - 2.82 (m, 1H), 2.34 - 2.14 (m, 2H), 2.09 - 1.95 (m, 1H), 1.77 - 1.52 (m , 2H), 1.01 (d, J=6.8 Hz, 3H), 0.46 (d, J=10.1 Hz, 1H). MS(ESI) m/z: 636.3 [M+H] ⁺ . Analytical HPLC (Method A): RT = 7.97 min, purity = >95.0%; Factor XIa Ki = 0.92 nM, plasma kallikrein Ki = 470 nM.

Example 106

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-3-( ^2H3 )methyl-9 _- methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), Preparation of 2(6),4,14,16-pentaen-8-one trifluoroacetate

Suspension 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidine-4 prepared as described in Intermediate 9 in ACN (1 ml) To a vial (4 ml) containing -ol (0.028 g, 0.089 mmol) was added HATU (0.044 g, 0.116 mmol) and DBU (0.020 ml, 0.134 mmol). After 20 min, (9R,13S)-13-amino-3-( ^2H3 )methyl-9-methyl-3,4,7,15-tetra prepared as described in Intermediate ₃₃ in DMF (1.0 ml) Azatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.027 g, 0.089 mmol) was added at room temperature. After 4 hours, the crude mixture was subjected to reverse phase chromatography (Phenomenex® Luna Axia C18 5μ 30 x 100 mm column, solvent A: 20% ACN - 80% H ₂ O - 0.1% TFA; solvent B: 80% ACN - 20 % H ₂ O - 0.1% TFA) to give (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl )phenyl]-6-oxo-1,6-dihydropyrimidin _- 1-yl}-3-( ^2H3 )methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3. 1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (19 mg, 28.6%) was obtained as a white solid. MS(ESI) m/z: 593.1 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.84 (s, 1H), 8.75 (d, J=5.0 Hz, 1H), 8.36 (s, 1H), 7.91 (d, J=2.5 Hz, 1H), 7.76 (dd, J=8.5, 2.2 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.56 - 7.50 (m, 2H), 6.39 (s, 1H), 6.01 ( dd, J=12.5, 4.0 Hz, 1H), 2.73 (td, J=6.6, 3.0 Hz, 1H), 2.32 (ddt, J=12.8, 8.6, 4.4 Hz, 1H), 2.13 - 1.99 (m, 2H) , 1.67 - 1.59 (m, 1H), 1.53 - 1.45 (m, 1H), 1.03 (d, J=6.9 Hz, 3H), 0.71 (br. s., 1H). Analytical HPLC (Method A): RT = 8.55 min, purity = 99.0%; Factor XIa Ki = 0.27 nM, plasma kallikrein Ki = 27 nM.

Example 107

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-( ^2H3 )methyl-9-methyl-3,4,7,15 _- tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

Suspension 6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl prepared as described in Intermediate 10 in ACN (1 ml) ]To a vial (4 ml) containing pyrimidin-4-ol hydrobromide (0.034 g, 0.083 mmol) was added HATU (0.041 g, 0.107 mmol) and DBU (0.034 ml, 0.223 mmol). After 30 min, (9R,13S)-13-amino-3-( ^2H ₃ )methyl-9-methyl-3,4,7,15-tetra prepared as described in Intermediate 33 in DMF (1.0 ml) Azatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.027 g, 0.089 mmol) was added at room temperature. After 2 hours, the crude mixture was subjected to reverse phase chromatography (Phenomenex® Luna Axia C18 5μ 30 x 100 mm column, solvent A: 20% ACN - 80% H ₂ O - 0.1% TFA; solvent B: 80% ACN - 20 % H ₂ O - 0.1% TFA) to give (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl )-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-( ^2H ₃ )methyl-9-methyl-3,4,7,15-tetraaza Tricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (20.3 mg, 32.2%) as a white solid. Obtained. MS(ESI) m/z: 611.2 (M+H) ⁺ and 613.1 (M+2+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.85 (s, 1H), 8.78 (d, J=5.1 Hz, 1H), 8.36 (s, 1H), 7.93 - 7.87 (m, 1H), 7.75 (s, 1H), 7.60 - 7.55 (m, 2H), 7.53 (s, 1H), 6.64 (s, 1H), 6.03 (dd, J=12.7, 4.1 Hz, 1H), 2.74 (td, J=6.6, 3.1 Hz) , 1H), 2.38 - 2.29 (m, 1H), 2.14 - 2.01 (m, 2H), 1.69 - 1.61 (m, 1H), 1.54 - 1.46 (m, 1H), 1.05 (d, J=7.0 Hz, 3H) ), 0.78 - 0.70 (m, 1H). Analytical HPLC (Method A): RT = 8.66 min, purity = 96.8%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 8 nM.

Example 108

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one

Suspension 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidine-4 prepared as described in Intermediate 9 in ACN (1 ml) To a vial (4 ml) containing -ol (0.023 g, 0.075 mmol) was added HATU (0.037 g, 0.097 mmol) and DBU (0.017 ml, 0.112 mmol). After 30 min, (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatri prepared as described in Intermediate 35 in DMF (1.0 ml) Cyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.025 g, 0.075 mmol) was added at room temperature. After stirring overnight, the crude mixture was concentrated and the residue was purified by reverse phase chromatography (Phenomenex® Luna Axia C18 5μ 30 x 100 mm column, solvent A: 20% ACN - 80% H ₂ O - 0.1% TFA; solvent B: purified by 80% ACN - 20% H ₂ O - 0.1% TFA) to give (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3 -triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triaza Tricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-8-one (11 mg, 22.4%) was obtained as a white solid. MS(ESI) m/z: 625.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.84 (s, 1H), 8.75 (d, J=5.0 Hz, 1H), 8.36 (s, 1H), 7.91 (d, J=2.5 Hz, 1H), 7.76 (dd, J=8.5, 2.2 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.56 - 7.50 (m, 2H), 6.39 (s, 1H), 6.01 ( dd, J=12.5, 4.0 Hz, 1H), 2.73 (td, J=6.6, 3.0 Hz, 1H), 2.32 (ddt, J=12.8, 8.6, 4.4 Hz, 1H), 2.13 - 1.99 (m, 2H) , 1.67 - 1.59 (m, 1H), 1.53 - 1.45 (m, 1H), 1.03 (d, J=6.9 Hz, 3H), 0.71 (br. s., 1H). Analytical HPLC (Method A): RT = 10.12 min, purity = 98.0%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 16 nM.

Example 109

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( Preparation of 18),2(6),4,14,16-pentaen-8-one

Suspension 6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl prepared as described in Intermediate 10 in ACN (1 ml) ]To a vial (4 ml) containing pyrimidin-4-ol (0.020 g, 0.060 mmol) was added HATU (0.030 g, 0.107 mmol) and DBU (0.014 ml, 0.090 mmol). After 30 min, (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatri prepared as described in Intermediate 35 in DMF (1.0 ml) Cyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.020 g, 0.060 mmol) was added at room temperature. After 2 hours, the crude mixture was subjected to reverse phase chromatography (Phenomenex® Luna Axia C18 5μ 30 x 100 mm column, solvent A: 20% ACN - 80% H ₂ O - 0.1% TFA; solvent B: 80% ACN - 20 % H ₂ O - 0.1% TFA) to give (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl )-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (7.5 mg, 19.1%) was obtained as a white solid. MS(ESI) m/z: 643.1 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.33 (s, 1H), 8.26 (s, 1H), 7.91 - 7.77 (m, 3H), 7.67 - 7.49 (m, 4H), 7.41 (d, J=7.7 Hz, 1H), 6.66 (s, 1H), 5.85 (dd, J=12.9, 3.2 Hz, 1H), 2.53 (td, J=6.8, 3.2 Hz, 1H), 2.43 - 2.34 (m, 1H), 2.21 - 2.10 (m, 1H), 1.98 - 1.88 (m, 1H), 1.65 - 1.53 (m, 2H), 1.29 - 1.15 (m, 4H). Analytical HPLC (Method A): RT = 10.18 min, purity = 98.5%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 5 nM.

Example 110

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

110A. tert-Butyl N-[(9R,13S)-3,9-dimethyl-8-oxo( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]Preparation of octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

tert-butyl N-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15 prepared as described in Intermediate 32E in CD ₃ OD (7 ml) under N ₂ -Tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (165 mg, 0.415 mmol) ) was added to the solution of Pd/C (44.2 mg, 0.042 mmol), and the resulting solution was recharged with N ₂ , purged, and recharged (3x) with D ₂ . The solution was stirred at room temperature and 50 psi D ₂ for 29 hours. The reaction mixture was filtered through Celite® and then through a syringe filter. The filtrate was concentrated to dryness and further dried under vacuum to give tert-butyl N-[(9R,13S)-3,9-dimethyl-8-oxo( ^10,11-2H ₂ )-3,4,7, 15-Tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate was obtained as a light brown solid. MS(ESI) m/z: 402.3 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.68 (d, J=5.3 Hz, 1H), 7.49 - 7.43 (m, 3H), 4.77 (dd, J=11.0, 5.3 Hz, 1H), 4.05 (s, 3H), 2.75 - 2.65 (m, 1H), 1.94 (br. s., 1H), 1.90 - 1.80 (m, 1H), 1.73 - 1.61 (m, 1H), 1.54 (t, J=5.8 Hz, 1H) ), 1.42 (s, 9H), 0.94 (d, J=6.8 Hz, 3H).

110B. (9R,13S)-13-amino-3,9-dimethyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( Preparation of 18),2(6),4,14,16-pentaen-8-one

CF ₃ COOD (0.230 ml, 2.99 mmol) was reacted with tert-butyl N-[(9R,13S)-3,9-dimethyl-8-oxo(10,11) in CD ₂ Cl ₂ (1 ml, 15.67 mmol) at room temperature. - ² H ₂ )-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-13- It was added to a solution of [1] carbamate (0.040 g, 0.100 mmol). After 1 hour, the reaction mixture was concentrated. The residue was dissolved in MeOH, free-based by passing through two successive resin-bound NaHCO ₃ cartridges (Stratosphere SPE; 500 mg, 0.90 mmol loading), and concentrated. (9R,13S)-13-amino-3,9-dimethyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1( 18),2(6),4,14,16-pentaen-8-one was carried over ‘as is’ to subsequent reactions. MS(ESI) m/z: 302.2 (M+H) ⁺ .

110C. (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

Suspension 6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl prepared as described in Intermediate 10 in ACN (1 ml) ]To a vial (4 ml) containing pyrimidin-4-ol (0.027 g, 0.083 mmol) was added HATU (0.041 g, 0.108 mmol) and DBU (0.019 ml, 0.124 mmol). After 30 min, (9R,13S)-13-amino-3,9-dimethyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo[12.3. 1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one was added at room temperature. After 2 hours, the crude mixture was subjected to reverse phase chromatography (Phenomenex® Luna Axia C18 5μ 30 x 100 mm column, solvent A: 20% ACN - 80% H ₂ O - 0.1% TFA; solvent B: 80% ACN - 20 % H ₂ O - 0.1% TFA) to give (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl )-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl(10,11- ² H ₂ )-3,4,7,15- Tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (22 mg, 35.9%) as white Obtained as a solid. MS(ESI) m/z: 610.2 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.84 (s, 1H), 8.77 (d, J=5.1 Hz, 1H), 8.35 (s, 1H), 7.88 (dd, J=8.7, 7.6 Hz, 1H) , 7.74 (s, 1H), 7.61 - 7.54 (m, 2H), 7.52 (s, 1H), 6.63 (s, 1H), 6.02 (dd, J=12.8, 4.0 Hz, 1H), 4.08 (s, 3H) ), 2.72 (t, J=6.8 Hz, 1H), 2.36 - 2.29 (m, 1H), 2.07 - 2.00 (m, 1H), 1.61 (t, J=6.3 Hz, 1H), 1.47 (d, J= 3.7 Hz, 1H), 1.03 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A): RT = 7.94 min, purity = 99.3%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 8 nM.

Example 111

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-( ^2H ₃ )methyl-9-methyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo[12.3 Preparation of .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

111A. tert-Butyl N-[(9R,13S)-3-( ² H ₃ )methyl-9-methyl-8-oxo(10,11- ² H ₂ ) _3,4,7,15 -tetraazatricyclo[ 12.3.1.0 Preparation of ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

under N ₂ tert-butyl N-[(9R,10E,13S)-3-( _2H3 )methyl-9-methyl-8-oxo-3, prepared as described in Example 33E in CD ₃ OD ( ⁷ ml) 4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate ( 153 mg, 0.382 mmol) was added to Pd/C (0.0382 mmol), the resulting solution was purged, recharged with N ₂ , then again with D ₂ (3x) and incubated at 50 psi D ₂ at room temperature. Stirred for 65 hours. The reaction mixture was filtered through Celite® and then through a syringe filter. The filtrate was concentrated to dryness and further dried under vacuum to obtain tert-butyl N-[(9R, _13S )-3-( ^2H3 )methyl-9-methyl-8-oxo( ^10,11-2H2 ₎ . _3,4,7,15 tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate is light brown. Obtained as a solid (143.4 mg, 88.2%). MS(ESI) m/z: 405.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.68 (d, J=5.1 Hz, 1H), 7.50 - 7.42 (m, 3H), 4.80 - 4.73 (m, 1H), 3.61 (q, J=7.0 Hz, 1H), 2.76 - 2.65 (m, 1H), 1.96 - 1.80 (m, 1H), 1.72 - 1.61 (m, 1H), 1.54 (t, J=5.6 Hz, 1H), 1.42 (s, 9H), 1.18 (t, J=7.0 Hz, 1H), 0.94 (d, J=7.0 Hz, 3H).

111B. (9R,13S)-13-amino-3-( ^2H ₃ )methyl-9-methyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ] Preparation of octadeca-1(18),2(6),4,14,16-pentaen-8-one

CF ₃ COOD (0.229 ml, 2.97 mmol) was dissolved in CD ₂ Cl ₂ (1 ml, 15.67 mmol) at room _temperature as tert-butyl N-[(9R,13S)-3-( ^2H3 )methyl-9-methyl. -8-oxo (10,11- ² H ₂ ) _3,4,7,15 -tetraazatricyclo [12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14, 16-pentaen-13-yl]carbamate (0.040 g, 0.099 mmol) was added. After 1 hour, the reaction mixture was concentrated to dryness. The residue was dissolved in MeOH, free-based by passing through two successive resin-bound NaHCO ₃ cartridges (Stratosphere SPE; 500 mg, 0.90 mmol loading), and concentrated. Product, (9R,13S)-13-amino-3-( ^2H ₃ )methyl-9-methyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one was carried over 'as is' to subsequent reactions. MS(ESI) m/z: 305.2 (M+H) ⁺ .

111C. (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-( ^2H ₃ )methyl-9-methyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo[12.3 Preparation of .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

Suspension 6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl prepared as described in Intermediate 10 in ACN (1 ml) ]To a vial (4 ml) containing pyrimidin-4-ol (0.027 g, 0.083 mmol) was added HATU (0.041 g, 0.108 mmol) and DBU (0.019 ml, 0.124 mmol). After 30 min, (9R _{, 13S)-13-amino-3-(2H3} ⁾ methyl-9-methyl( ^10,11-2H2 )-3,4,7,15- in DMF (1.0 ml) Tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.025 g, 0.082 mmol) was added at room temperature. After 2 hours, the crude mixture was subjected to reverse phase chromatography (Phenomenex® Luna Axia C18 5μ 30 x 100 mm column, solvent A: 20% ACN - 80% H ₂ O - 0.1% TFA; solvent B: 80% ACN - 20 % H ₂ O - 0.1% TFA) to give (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl )-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-( ^2H ₃ )methyl-9-methyl( ^10,11-2H ₂ )-3 ,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (19.2 mg, 30.8%) was obtained as a white solid. MS(ESI) m/z: 613.2 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.90 - 8.75 (m, 2H), 8.35 (s, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.76 (br. s., 1H), 7.64 - 7.52 (m, 3H), 6.63 (s, 1H), 6.00 (d, J=12.1 Hz, 1H), 2.76 - 2.68 (m, 1H), 2.37 - 2.29 (m, 1H), 2.08 - 2.02 (m , 1H), 1.61 (t, J=6.2 Hz, 1H), 1.46 (d, J=4.4 Hz, 1H), 1.03 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A): RT = 7.90 min, purity = 99.1%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 8 nM.

Example 112

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo[12.3 Preparation of .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

112A. tert-Butyl N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo Preparation of [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate.

tert-Butyl N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo prepared as described in Example 30E in CD ₃ OD (7 ml) under N ₂ -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]car To barmate (180 mg, 0.415 mmol) was added Pd/C (0.0415 mmol), and the resulting solution was purged, recharged with N ₂ , recharged with D ₂ (3x), and then incubated at 50 psi at room temperature. It was stirred at D ₂ for 60 hours. The reaction mixture was filtered through Celite® and then through a syringe filter. _{The filtrate was concentrated to dryness and further dried under vacuum to obtain tert-butyl N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo(10,11-2H 2} ⁾ -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate was obtained as a light brown solid (167 mg, 88.9%). MS(ESI) m/z: 438.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.70 (d, J=5.5 Hz, 1H), 7.79 (s, 1H), 7.72 (s, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.52 - 7.44 (m, 4H), 3.61 (q, J=7.0 Hz, 1H), 2.69 (t, J=6.8 Hz, 2H), 1.91 - 1.82 (m, 2H), 1.74 - 1.64 (m, 2H), 1.53 (t, J=5.8 Hz, 2H), 1.42 (s, 13H), 1.33 - 1.14 (m, 6H), 0.94 (d, J=7.0 Hz, 6H).

112B. (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ] Preparation of octadeca-1(18),2(6),4,14,16-pentaen-8-one

CF ₃ COOD (0.211 ml, 2.74 mmol) was solution tert-butyl N-[(9R,13S)-3-(difluoromethyl)-9-methyl in CD ₂ Cl ₂ (1 ml, 15.67 mmol) at room temperature. -8-oxo(10,11- ² H ₂ )-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14 ,16-pentaen-13-yl]carbamate (0.040 g, 0.091 mmol) was added. After 1 hour, the reaction mixture was concentrated to dryness. The residue was dissolved in MeOH, free-based by passing through two successive resin-bound NaHCO ₃ cartridges (Stratosphere SPE; 500 mg, 0.90 mmol loading), and concentrated. Product, (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one was carried over as is to the subsequent reaction. MS(ESI) m/z: 338.2 (M+H) ⁺ .

112C. (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo[12.3 Preparation of .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate.

Suspension 6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl prepared as described in Intermediate 10 in ACN (1 ml) ]To a vial (4 ml) containing pyrimidin-4-ol (0.024 g, 0.074 mmol) was added HATU (0.037 g, 0.096 mmol) and DBU (0.017 ml, 0.111 mmol). After 30 min, (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl( ^10,11-2H2 )-3,4,7,15- in DMF (1.0 _ml ) Tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.025 g, 0.074 mmol) was added at room temperature. After 2 hours, the crude mixture was subjected to reverse phase chromatography (Phenomenex® Luna Axia C18 5μ 30 x 100 mm column, solvent A: 20% ACN - 80% H ₂ O - 0.1% TFA; solvent B: 80% ACN - 20 % H ₂ O - 0.1% TFA) to give (9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl )-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl( ^10,11-2H ₂ )-3 ,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (16.8 mg, 29.8%) was obtained as a white solid. MS(ESI) m/z: 646.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.91 (s, 1H), 8.78 (d, J=5.1 Hz, 1H), 8.34 (s, 1H), 7.91 - 7.85 (m, 1H), 7.83 - 7.67 ( m, 3H), 7.58 - 7.52 (m, 2H), 6.63 (s, 1H), 6.04 (dd, J=12.8, 4.6 Hz, 1H), 2.73 (quin, J=6.8 Hz, 1H), 2.31 (td) , J=12.8, 4.0 Hz, 1H), 2.07 - 1.99 (m, 1H), 1.59 (t, J=6.1 Hz, 1H), 1.48 (d, J=4.8 Hz, 1H), 1.01 (d, J= 6.8 Hz, 3H). Analytical HPLC (Method A): RT = 8.81 min, purity = 100%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 6 nM.

Example 113

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]Preparation of octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]Octadeca-1(18),2(6),4,14,16-pentaen-8-one was prepared in Intermediate 9 in a manner similar to the procedure described in Example 112, 6-(5-chloro- Prepared using 2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (0.023 g, 0.075 mmol), (9R,13S)-13 -{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl }-3-(difluoromethyl)-9-methyl( ^10,11-2H ₂ )-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18 ),2(6),4,14,16-pentaen-8-one trifluoroacetate was obtained as a white solid (20.4 mg, 36.3%). MS(ESI) m/z: 628.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) 8.91 (s, 1H), 8.77 (d, J=5.1 Hz, 1H), 8.36 (s, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.83 - 7.65 (m, 5H), 7.58 - 7.52 (m, 1H), 6.39 (d, J=0.4 Hz, 1H), 6.03 (dd, J=12.8, 4.6 Hz, 1H), 2.74 (t, J=6.7 Hz) , 1H), 2.32 (td, J=12.9, 4.0 Hz, 1H), 2.07 - 1.98 (m, 1H), 1.59 (t, J=6.2 Hz, 1H), 1.48 (d, J=4.8 Hz, 1H) , 1.02 (d, J=7.0 Hz, 3H). Analytical HPLC (Method A): RT = 8.81 min, purity = 99.3%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 25 nM.

Example 114

(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-10-methyl-3,8,16-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15, Preparation of 17-hexaen-9-one, bis-trifluoroacetate

Suspension 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidine-4 prepared as described in Intermediate 9 in ACN (1 ml) To a vial (4 ml) containing -ol (0.021 g, 0.067 mmol) was added HATU (0.033 g, 0.088 mmol) and DBU (0.015 ml, 0.101 mmol). After 30 min, (10R,14S)-14-amino-10-methyl-3,8,16-triazatricyclo[13.3.1.0 ^2,7 ] prepared as described in Intermediate 38 in DMF (1.0 ml) Nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one (0.020 g, 0.067 mmol) was added at room temperature. After 4 hours, the crude mixture was subjected to reverse phase chromatography (Phenomenex® Luna Axia C18 5μ 30 x 100 mm column, solvent A: 20% ACN - 80% H ₂ O - 0.1% TFA; solvent B: 80% ACN - 20 % H ₂ O - 0.1% TFA) to give (10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl )phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8,16-triazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19 ),2(7),3,5,15,17-hexaen-9-one, bis-trifluoroacetate (3.7 mg, 6.72%) was obtained as a white solid. MS(ESI) m/z: 587.1 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 9.02 (s, 1H), 8.77 (d, J=4.8 Hz, 1H), 8.66 (d, J=4.8 Hz, 1H), 8.37 (s, 1H), 7.94 - 7.88 (m, 2H), 7.79 - 7.74 (m, 2H), 7.71 - 7.67 (m, 2H), 7.59 (dd, J=8.1, 4.8 Hz, 1H), 6.39 (s, 1H), 6.09 (dd , J=12.8, 5.1 Hz, 1H), 2.76 (br. s., 1H), 2.28 (t, J=12.8 Hz, 1H), 2.10 - 2.03 (m, 2H), 1.62 - 1.53 (m, 2H) , 1.01 (d, J=7.0 Hz, 3H), 0.66 (br. s., 1H). Analytical HPLC (Method A): RT = 7.60 min, purity = 99.0%; Factor XIa Ki = 3.3 nM, plasma kallikrein Ki = 200 nM.

Example 115

(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3- ( ² H ₃ )methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16- Preparation of pentaen-8-one trifluoroacetate

Suspension prepared as described in Intermediate 22 in ACN (1 ml) containing 6-(5-chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol (0.017 g, 0.066 mmol) HATU (0.033 g, 0.086 mmol) and DBU (0.015 ml, 0.099 mmol) were added to a vial (4 ml). After 30 min, (9R,13S)-13-amino-3-( ^2H ₃ )methyl-9-methyl-3,4,7,15-tetra prepared as described in Intermediate 33 in DMF (1.0 ml) Azatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.020 g, 0.066 mmol) was added at room temperature. After 4 hours, the crude mixture was subjected to reverse phase chromatography (Phenomenex® Luna Axia C18 5μ 30 x 100 mm column, solvent A: 20% ACN - 80% H ₂ O - 0.1% TFA; solvent B: 80% ACN - 20 % H ₂ O - 0.1% TFA) to give (9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6 -dihydropyrimidin-1-yl]-3-( ^2H3 )methyl-9-methyl-3,4,7,15 _- tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18 ),2(6),4,14,16-pentaen-8-one trifluoroacetate (7.2 mg, 16.3%) was obtained as a white solid. MS(ESI) m/z: 587.1 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.81 (d, J=5.3 Hz, 1H), 8.11 (s, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.87 (s, 1H), 7.66 (d, J=5.1 Hz, 1H), 7.59 - 7.55 (m, 1H), 7.50 (d, J=1.8 Hz, 1H), 6.80 (s, 1H), 6.10 (dd, J=12.4, 4.1 Hz, 1H), 4.01 - 3.96 (m, 3H), 2.76 (dd, J=6.6, 3.1 Hz, 1H), 2.51 - 2.46 (m, 1H), 2.22 - 2.11 (m, 2H) , 1.72 - 1.67 (m, 1H), 1.56 (br. s., 1H), 1.08 (d, J=7.0 Hz, 3H), 0.85 (br. s., 1H). Analytical HPLC (Method A): RT = 7.41 min, purity = 100.0%.; Factor XIa Ki = 113 nM.

Example 116

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidine- 1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 Preparation of ,14,16-pentaen-8-one

Suspension 6-[5-chloro-2-(1H-1,2,3-triazol-1-yl) phenyl]pyrimidin-4-ol (0.016) prepared as described in Intermediate 8 in ACN (1 ml) g, 0.060 mmol) were added HATU (0.030 g, 0.078 mmol) and DBU (0.014 ml, 0.090 mmol). After 30 min, (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatri prepared as described in Intermediate 35 in DMF (1.0 ml) Cyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.020 g, 0.060 mmol) was added at room temperature. After 4 hours, the crude mixture was subjected to reverse phase chromatography (Phenomenex® Luna Axia C18 5μ 30 x 100 mm column, solvent A: 20% ACN - 80% H ₂ O - 0.1% TFA; solvent B: 80% ACN - 20 % H ₂ O - 0.1% TFA) to give (9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6 -dihydropyrimidin-1-yl]-3-( ^2H3 )methyl-9-methyl-3,4,7,15 _- tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18 ),2(6),4,14,16-pentaen-8-one was obtained as a white solid. MS(ESI) m/z: 591.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.22 (d, J=1.8 Hz, 2H), 7.90 - 7.72 (m, 5H), 7.66 - 7.50 (m, 4H), 7.41 (d, J=7.5 Hz, 1H), 6.27 (s, 1H), 5.83 (dd, J=12.9, 3.4 Hz, 1H), 2.57 - 2.47 (m, 1H), 2.41 - 2.31 (m, 1H), 2.18 - 2.06 (m, 1H) , 1.90 (dd, J=9.5, 5.1 Hz, 1H), 1.64 - 1.52 (m, 2H), 1.27 - 1.11 (m, 4H). Analytical HPLC (Method A): RT = 8.82 min, purity = 98.4%; Factor XIa Ki = 0.72 nM, plasma kallikrein Ki = 120 nM.

Example 117

(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3- (difluoromethyl)-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene Preparation of -8-one

A suspension of 6-(5-chloro-1-methyl-1H-indazol-7-yl) pyrimidin-4-ol (0.016 g, 0.060 mmol) prepared as described in Intermediate 22 in ACN (1 ml) HATU (0.030 g, 0.078 mmol) and DBU (0.014 ml, 0.090 mmol) were added to the vial (4 ml) containing. After 30 min, (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatri prepared as described in Intermediate 35 in DMF (1.0 ml) Cyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.020 g, 0.060 mmol) was added at room temperature. After 4 hours, the crude mixture was subjected to reverse phase chromatography (Phenomenex® Luna Axia C18 5μ 30 x 100 mm column, solvent A: 20% ACN - 80% H ₂ O - 0.1% TFA; solvent B: 80% ACN - 20 % H ₂ O - 0.1% TFA) to give (9R,13S)-13-[4-(5-chloro-1-methyl-1H-indazol-7-yl)-6-oxo-1,6 -dihydropyrimidin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1 (18), 2(6),4,14,16-pentaen-8-one (11 mg, 30.2%) was obtained as a white solid. MS(ESI) m/z: 578.2 (M+H) ⁺ .

^1H NMR (400MHz, CD ₃ OD) δ 8.36 (s, 1H), 7.95 (s, 1H), 7.79 - 7.74 (m, 2H), 7.66 (s, 1H), 7.54 - 7.38 (m, 4H), 7.34 (d, J=2.0 Hz, 1H), 6.67 (s, 1H), 5.83 (dd, J=13.0, 3.3 Hz, 1H), 3.79 (s, 3H), 2.41 - 2.32 (m, 2H), 2.11 (d, J=12.5 Hz, 1H), 1.83 - 1.76 (m, 1H), 1.53 - 1.45 (m, 2H), 1.16 - 1.03 (m, 4H). Analytical HPLC (Method A): RT = 9.56 min, purity = 100%; Factor XIa Ki = 90 nM, plasma kallikrein Ki = 3,800 nM.

Example 118

(10R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-10-methyl-3,8,16-triazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3 , 5,15,17-hexaen-9-one bis-trifluoroacetate production

Suspension 6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl prepared as described in Intermediate 10 in ACN (1 ml) ]To a vial (4 ml) containing pyrimidin-4-ol (0.028 g, 0.084 mmol) was added HATU (0.042 g, 0.11 mmol) and DBU (0.019 ml, 0.127 mmol). After 30 min, (10R,14S)-14-amino-10-methyl-3,8,16-triazatricyclo[13.3.1.0 ^2,7 ] prepared as described in Intermediate 39 in DMF (1.0 ml) Nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one (0.025 g, 0.084 mmol) was added at room temperature. After stirring overnight, the crude mixture was subjected to reverse phase chromatography (Phenomenex® Luna Axia C18 5μ 30 x 100 mm column, solvent A: 20% ACN - 80% H ₂ O - 0.1% TFA; solvent B: 80% ACN - Purified by (20% H ₂ O - 0.1% TFA), concentrated and lyophilized, (10R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3 -triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10-methyl-3,8,16-triazatricyclo [13.3 .1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one, bis-trifluoroacetate (13 mg, 17.6%) as a white solid. It was obtained as. MS(ESI) m/z: 611.2 (M+H) ⁺ and 613.1 (M+2+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ ¹ H NMR (500 MHz, CD ₃ OD-d4) d 8.98 (s, 1H), 8.86 - 8.83 (m, 1H), 8.75 - 8.71 (m, 1H), 8.37 (s, 1H), 7.98 (s, 1H), 7.95 - 7.87 (m, 2H), 7.79 - 7.71 (m, 2H), 7.59 - 7.57 (m, 1H), 6.64 (s, 1H), 6.08 (dd , J=12.4, 5.0 Hz, 1H), 2.77 (br. s., 1H), 2.35 - 2.28 (m, 1H), 2.13 - 2.02 (m, 2H), 1.61 - 1.55 (m, 2H), 1.29 ( d, J=6.9 Hz, 1H), 1.00 (d, J=7.2 Hz, 3H), 0.66 (br. s., 1H). Analytical HPLC (Method A): RT = 7.11 min, purity = 97.5%; Factor XIa Ki = 1.4 nM, plasma kallikrein Ki = 73 nM.

Example 119

(9R,13S)-3-(difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethyl)-1H-1,2,3-tria zol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,14,16-pentaen-8-one

119A. Preparation of 4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

2-Bromo-4-methylaniline (3 g, 16.12 mmol), bis(pinacolato)diborone (6.14 g, 24.19 mmol), and KOAc (4.07 g, 41.4 mmol) were dissolved in DMSO (9 mL) with N ₂ Added under atmosphere and then degassed for 10 minutes. Pd(dppf)Cl ₂ .CH ₂ Cl ₂ adduct (0.395 g, 0.484 mmol) was added and the resulting suspension was stirred at 80° C. overnight. The reaction mixture was partitioned between DCM and water. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by normal phase chromatography using hexane and EtOAc as eluents to give 4-methyl-2-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.52 g, 94% yield) was obtained as a clear oil, which solidified into a white solid on standing. MS(ESI) m/z: 152.3 (MC ₆ H ₁₀ +H) ⁺ .

^1H NMR (400MHz, CDCl ₃ -d) δ 7.43 (d, J=1.8 Hz, 1H), 7.04 (dd, J=8.3, 2.3 Hz, 1H), 6.55 (d, J=8.1 Hz, 1H), 4.60 (br. s., 2H), 2.23 - 2.20 (m, 3H), 1.38 - 1.32 (m, 12H).

119B. Preparation of 2-(6-methoxypyrimidin-4-yl)-4-methylaniline

4-Chloro-6-methoxypyrimidine (1.55 g, 10.72 mmol), 4-methyl-2-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.5 g, 10.72 mmol) and 2 M aqueous Na ₂ CO ₃ (5.36 mL, 10.72 mmol) were added. The mixture was purged with Ar for 10 minutes, then PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.876 g, 1.072 mmol) was added and the reaction mixture was heated at 90°C. After 2 hours, the reaction was diluted with water and extracted with EtOAc. The organic layer was washed with brine and concentrated to give a brown oil. The crude product was purified by normal phase chromatography using heptane and EtOAc as eluents to give 2-(6-methoxypyrimidin-4-yl)-4-methylaniline (670 mg, 29%) as a solid. MS(ESI) m/z: 216.1 (M+H) ⁺ .

¹ H NMR (500 MHz, CDCl ₃ -d) δ 8.79 (d, J=1.1 Hz, 1H), 7.33 (d, J=1.4 Hz, 1H), 7.08 - 7.01 (m, 2H), 6.67 (d, J =8.3 Hz, 1H), 5.68 (br. s., 2H), 4.03 (s, 3H), 2.29 (s, 3H).

119C. Preparation of 4-methoxy-6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidine

To a cooled (0° C.), clear yellow solution of 2-(6-methoxypyrimidin-4-yl)-4-methylaniline (0.670 g, 3.11 mmol) in ACN (44.5 mL) was added isoamylnitrite (0.63 mL, 4.67 mmol) was added, followed by TMSN ₃ (0.62 mL, 4.67 mmol) dropwise. After 10 minutes, the cooling bath was removed and the reaction was allowed to warm to room temperature. After 4.5 hours, Cu ₂ O (0.045 g, 0.311 mmol) was added. After a few minutes, 3,3,3-trifluoroprop-1-yne (0.293 g, 3.11 mmol) gas was bubbled into the dark green solution at room temperature. After 1 hour, the reaction was diluted with DCM, washed with saturated NH ₄ Cl, brine, dried over MgSO ₄ , filtered and concentrated to give a brown oil. The crude product was purified by normal phase chromatography using heptane and EtOAc as eluents to give 4-methoxy-6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3- Triazol-1-yl)phenyl)pyrimidine (941 mg, 90%) was obtained as a solid. MS(ESI) m/z: 336.1 (M+H) ⁺ .

^1H NMR (500MHz, CDCl ₃ -d) δ 8.63 (s, 1H), 7.98 (s, 1H), 7.56 (s, 1H), 7.45 (s, 2H), 6.58 (s, 1H), 3.97 (s) , 3H), 2.53 (s, 3H).

119D. Preparation of 6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl) pyrimidin-4-ol

4-methoxy-6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3- in AcOH (14.03 mL) and 48% aqueous HBr (15.88 mL, 140 mmol) A clear yellow solution of triazol-1-yl)phenyl)pyrimidine (0.941 g, 2.81 mmol) was warmed to 85°C. After 3 hours, the reaction was cooled to room temperature and concentrated. The yellow gum was dissolved in EtOAc, washed with saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated. Et ₂ O (3 mL) was added, sonicated and filtered. The solid was rinsed with Et ₂ O (5 mL) and air-dried under suction overnight to give 6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazole-1 -yl)phenyl)pyrimidin-4-ol (0.609 g, 67.5% yield) was obtained as a pale yellow solid. MS(ESI) m/z: 322.1 (M+H) ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) d 12.90 (br. s., 1H), 8.06 (s, 1H), 7.93 (d, J=0.7 Hz, 1H), 7.57 - 7.40 (m, 3H), 6.51 ( d, J=0.9 Hz, 1H), 2.53 (s, 3H).

119E. (9R,13S)-3-(difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethyl)-1H-1,2,3-tria zol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-3-(difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethyl)-1H-1,2,3-tria zol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,17-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (13 mg, 23%) was reacted with 6-(5-methyl in a manner similar to that described in Example 56. -2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol and (9R,13S) prepared as described in Intermediate 37 -13-amino-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6) , prepared using 4,14,16-pentaen-8-one. MS(ESI) m/z: 640.2 (M+H) ⁺ .

^1H NMR (400MHz, CD ₃ OD) δ 8.67 (s, 1H), 8.62 - 8.57 (m, 1H), 8.31 - 8.10 (m, 3H), 8.00 - 7.83 (m, 2H), 7.69 (s, 2H) ), 7.45 (d, J=0.9 Hz, 2H), 7.02 (dd, J=5.1, 1.5 Hz, 1H), 6.39 (s, 1H), 5.71 - 5.62 (m, 1H), 2.60 - 2.53 (m, 1H), 2.42 (s, 3H), 2.27 (d, J=6.6 Hz, 1H), 2.03 - 1.93 (m, 2H), 1.56 (dd, J=13.4, 5.1 Hz, 1H), 1.31 - 1.19 (m , 2H), 1.03 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A): RT = 8.90 min, purity = 99%; Factor XIa Ki = 1.1 nM, plasma kallikrein Ki = 340 nM.

Example 120

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-5-(trifluoromethyl)- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one

The TFA/DMSO solution was prepared by dissolving TFA (10 μL) in DMSO (2.5 mL). (9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo- prepared as described in Example 133 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2( 6),4,14,16-pentaen-8-one trifluoroacetate (0.0084 g, 0.013 mmol), and individual vials containing a mixture of Zn(SO ₂ CF ₃ ) ₂ (8.31 mg, 0.025 mmol) DMSO (0.25 mL) was added. Next, 0.25 mL of TFA/DMSO solution was added to obtain a clear yellow solution. Then 70% aqueous t-BuOOH (5.21 μl, 0.038 mmol) was added. After 2 hours, additional Zn(SO ₂ CF ₃ ) ₂ (16.6 mg, 0.050 mmol) was added. After 30 minutes, additional 70% aqueous t-BuOOH (10.4 μl, 0.076 mmol) was added. After 1 hour, the reaction was stopped. MeOH (1.5 mL) was added to the reaction mixture, which was purified by reverse phase chromatography to give (9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazole- 1-yl) phenyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraaza Tricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.0024 g, 30% yield) was obtained as a white solid. MS(ESI) m/z: 624.4 (M+H) ⁺ , 626.4 (M+2+H) ⁺ . The mixture of atropisomers was observed by 1H NMR and ¹⁹ F NMR.

¹ H NMR (500MHz, CD ₃ OD) δ 9.09 - 9.06 (m, 0.5H), 9.03 - 9.00 (m, 0.5H), 8.75 (d, J=5.0 Hz, 0.5H), 8.72 (d, J= 5.0 Hz, 0.5H), 8.33 (s, 0.5H), 8.25 (s, 0.5H), 7.87 (br. s., 0.5H), 7.80 (br. s., 0.5H), 7.76 - 7.67 (m , 3H), 7.64 (d, J=2.2 Hz, 0.5H), 7.61 (d, J=2.2 Hz, 0.5H), 7.55 - 7.48 (m, 2H), 6.06 - 5.97 (m, 1H), 4.06 ( s, 1.5H), 4.05 (s, 1.5H), 2.77 - 2.68 (m, 1H), 2.33 - 2.24 (m, 1H), 2.14 - 1.99 (m, 2H), 1.65 - 1.56 (m, 1H), 1.56 - 1.44 (m, 1H), 1.02 - 0.97 (m, 3H), 0.68 - 0.55 (m, 1H). ¹⁹ F NMR (471 MHz, CD ₃ OD) δ -60.90 (s, 1F), -60.94 (s, 1F). Analytical HPLC (Method A): RT = 7.55 min, purity = 97.9%; Factor XIa Ki = 110 nM.

Example 121

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10-methyl-3,8,16-triazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2(7),3 , 5,15,17-hexaen-9-one, production of bis-trifluoroacetate

Suspension 6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl prepared as described in Intermediate 15 in ACN (2 ml) }To a vial (4 ml) containing pyrimidin-4-ol (0.027 g, 0.078 mmol) was added HATU (0.038 g, 0.101 mmol) and DBU (0.018 ml, 0.116 mmol). After 30 min, (10R,14S)-14-amino-10-methyl-3,8,16-triazatricyclo[13.3.1.0 ^2,7 ] prepared as described in Intermediate 39 in ACN (1.0 ml) Nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one (0.023 g, 0.078 mmol) was added at room temperature. After 4 hours, the crude mixture was subjected to reverse phase chromatography (Phenomenex® Luna Axia C18 5μ 30 x 100 mm column, solvent A: 20% ACN - 80% H ₂ O - 0.1% TFA; solvent B: 80% ACN - 20 % H ₂ O - 0.1% TFA) to give (10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-tria zol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-3,8,16-triazatricyclo[13.3.1.0 ^2,7 ]nona Deca-1(19),2(7),3,5,15,17-hexaen-9-one, bis-trifluoroacetate (18 mg, 26.8%) was obtained as a white solid. MS(ESI) m/z: 621.2 (M+H) ⁺ and 623.1 (M+2+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.82 (s, 1H), 8.72 (d, J=0.8 Hz, 1H), 8.63 (d, J=5.0 Hz, 1H), 8.54 (dd, J=5.0, 1.4 Hz, 1H), 7.80 - 7.78 (m, 2H), 7.70 (dd, J=8.1, 1.5 Hz, 1H), 7.68 - 7.64 (m, 1H), 7.61 - 7.57 (m, 2H), 7.51 (dd , J=8.0, 5.0 Hz, 1H), 6.33 (d, J=0.8 Hz, 1H), 5.95 (dd, J=12.7, 4.7 Hz, 1H), 2.66 - 2.61 (m, 1H), 2.13 (t, J=12.7 Hz, 1H), 1.91 (t, J=9.9 Hz, 2H), 1.47 - 1.39 (m, 2H), 0.87 (d, J=7.2 Hz, 3H). Analytical HPLC (Method A): RT = 8.18 min, purity = 98.3%; Factor XIa Ki = 2.8 nM, plasma kallikrein Ki = 190 nM.

Example 122

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), Preparation of 2(6),4,14,16-pentaen-8-one

Suspension 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidine-4 prepared as described in Intermediate 9 in ACN (1 ml) To a vial (4 ml) containing -ol (0.014 g, 0.046 mmol) was added HATU (0.019 g, 0.051 mmol) and DBU (0.009 ml, 0.060 mmol). After 20 min, (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,16-tetra prepared as described in Intermediate 43 in DMF (1.0 ml) Azatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.0155 g, 0.046 mmol) was added at room temperature. After 3 hours, the crude mixture was reversed phase (Phenomenex® Luna Axia C18 _5μ 30 ₂ O - 0.1% TFA) to give (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl ]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (1.7 mg, 5.86%) was obtained. MS(ESI) m/z: 626 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.35 (s, 1H), 8.74 (s, 1H), 8.63 (d, J=1.7 Hz, 1H), 8.60 - 8.53 (m, 2H), 8.12 - 7.97 (m, 2H), 7.93 - 7.86 (m, 2H), 7.85 - 7.71 (m, 2H), 6.41 (s, 1H), 5.57 (d, J=9.9 Hz, 1H), 2.46 - 2.39 (m, 1H) ), 2.04 - 1.95 (m, 1H), 1.79 (d, J=10.7 Hz, 1H), 1.42 (d, J=6.9 Hz, 1H), 1.24 (br. s., 1H), 0.99 (d, J =6.6 Hz, 4H). Analytical HPLC (Method C): RT = 1.52 min, purity = 100.0%; Factor XIa Ki = 0.16 nM, plasma kallikrein Ki = 34 nM.

Example 123

6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S)-3,9- Dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-3 , Preparation of 4-dihydropyrimidin-4-one

123A. (9R,13S)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16 -Preparation of pentaen-13-amine

(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] prepared as described in Intermediate 32 in THF (3022 μl) BH ₃ .THF complex (1813 μl, 1.813 mmol) in a solution of octadeca-1(18),2(6),4,14,16-pentaen-8-one dihydrochloride (45 mg, 0.121 mmol) was added. The reaction was sealed and heated at 60°C for 4.5 hours. MeOH was added followed by 1.25 M HCl in MeOH (2 ml). The mixture was sealed and heated at 60° C. for 1 hour. Another 0.5 mL of HCl in MeOH was added and heated at 60° C. for 1 hour and then cooled to room temperature overnight. Another 0.5 mL of 4 N HCl in dioxane was added and the solution was heated at 65° C. for 5 hours. The reaction mixture was concentrated. The residue was dissolved in MeOH and purified by reverse phase preparative HPLC. Concentrated and passed through NaHCO ₃ cartridge, (9R,13S)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18) ,2(6),4,14,16-pentaen-13-amine (28 mg, 81%) was obtained as a colorless oil. MS(ESI) m/z: 286.5 (M+H) ⁺ .

123B. 6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S)-3,9- Dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-3 , Preparation of 4-dihydropyrimidin-4-one

6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S)-3,9- Dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-3 ,4-dihydropyrimidin-4-one trifluoroacetate (12.5 mg, 30.4% yield) was purified into (9R,13S)-3,9-dimethyl-3,4, in a manner similar to the procedure described in Example 56. 7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-amine (6.5 mg, 0.020 mmol) was used. It was manufactured.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.95 (s, 1H), 8.84 (d, J=5.1 Hz, 1H), 8.35 (s, 1H), 8.09 - 8.04 (m, 1H), 7.90 - 7.83 (m , 1H), 7.64 (s, 1H), 7.59 - 7.53 (m, 2H), 6.62 (s, 1H), 6.17 (dd, J=12.5, 4.8 Hz, 1H), 4.02 (s, 3H), 2.97 ( d, J=10.6 Hz, 1H), 2.53 (br. s., 1H), 2.34 - 2.19 (m, 1H), 2.17 - 2.05 (m, 1H), 2.04 - 1.75 (m, 2H), 1.56 (t) , J=12.3 Hz, 1H), 1.23 (br. s., 1H), 0.86 (d, J=7.3 Hz, 3H), 0.75 - 0.40 (m, 1H). MS(ESI) m/z: 594.2 (M+H) ⁺ . Analytical HPLC (Method A): RT = 6.97 min, purity = 99.1%; Factor XIa Ki = 2 nM, plasma kallikrein Ki = 690 nM.

Example 124

(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-10-fluoro-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( Preparation of 18),2(6),4,14,16-pentaen-8-one

124A. tert-Butyl N-[(9S,13S)-3-(difluoromethyl)-10-fluoro-9-methyl-8-oxo 3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]Preparation of octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

Fe ₂ (C ₂ O ₄ ) ₃ .6H ₂ O (2.797 g, 5.78 mmol) was added to RBF containing H ₂ O (30 ml). The suspension was warmed by water bath (50° C.) to aid dissolution. After 3 hours, the clear yellow solution was cooled to 0°C and purged with Ar. After 20 minutes, SELECTFLUOR® (2.048 g, 5.78 mmol) in ACN (5 ml) was added followed by tert-butyl N-[( 9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18), 2(6),4,10,14,16-hexaen-13-yl]carbamate (0.500 g, 1.156 mmol) was added dropwise. After 5 minutes, NaBH ₄ (0.350 g, 9.25 mmol) was added in two separate portions over a 5 minute period. After 15 minutes, the reaction mixture was allowed to reach room temperature. After 1 hour, the reaction mixture was quenched with aqueous NH ₄ OH (28-30%; 15 mL). After 30 minutes, the reaction mixture was filtered and the collected solid was washed with EtOAc. The combined organics were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a crude mixture of isomers. The material was subjected to chiral _purification using Chiralpak® IC, 21 The initial eluted isomer was tert-butyl N-[(9S,13S)-3-(difluoromethyl)-10-fluoro-9-methyl-8-oxo-3,4,7-triazatricyclo[ 12.3.1.0 was assigned as ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (99.5% ee; 38 mg, 7.26%) , the second eluting isomer is tert-butyl N-[(9R,13S)-3-(difluoromethyl)-11-fluoro-9-methyl-8-oxo-3,4,7-triazatricyclo Assigned as [12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (99.5% ee; 34 mg, 6.50%) It has been done. MS(ESI) m/z: 397 (M-tBu) ⁺ .

124B. (9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-10-fluoro-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-8-one

Initially eluted isomer tert-butyl N-[(9S,13S)-3-(difluoromethyl)-10-fluoro-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.038 g, 0.084 mmol) was dissolved in HCl (4.0 M in dioxane). ) (0.420 ml, 1.680 mmol). A minimal amount of MeOH was added to assist dissolution. After 2 hours, the reaction mixture was concentrated to dryness. The residue was dissolved in MeOH and passed through a NaHCO ₃ cartridge (Stratosphere SPE; 500 mg, 0.90 mmol loading). The filtrate was concentrated and the organic base was temporarily set aside. Separately, 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidine prepared as described in Intermediate 9 in ACN (1.120 ml) To a flask containing a white suspension of -4-ol (0.026 g, 0.084 mmol) was added HATU (0.035 g, 0.092 mmol) and DBU (0.016 ml, 0.109 mmol). After 20 minutes, free base (1 mL) in DMF was added and the resulting suspension was stirred at room temperature overnight. The reaction mixture was _subjected to reverse phase chromatography (Sunfire C18 5μ ₃₀ - 0.1% TFA). The pure fraction was liberated from the organic portion and the remaining aqueous phase was freeze-dried to obtain (9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazole). -1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-10-fluoro-9-methyl-3,4,7- Triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (18.2 mg, 33.3%) was obtained as a white solid. . MS(ESI) m/z: 643 (M+H) ⁺ .

¹ H NMR (500 MHz, CD ₃ OD) δ 8.83 (s, 1H), 8.40 - 8.38 (m, 1H), 7.93 (d, J=2.2 Hz, 1H), 7.80 - 7.75 (m, 2H), 7.71 - 7.68 (m, 1H), 7.66 - 7.62 (m, 3H), 7.54 (d, J=7.7 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 6.46 (d, J=0.8 Hz, 1H) ), 5.92 (dd, J=13.3, 4.5 Hz, 1H), 5.38 - 5.25 (m, 1H), 3.19 - 3.14 (m, 1H), 2.48 - 2.41 (m, 1H), 2.27 (ddt, J=12.9 , 8.7, 4.2 Hz, 1H), 1.85 - 1.75 (m, 1H), 1.05 (d, J=6.9 Hz, 3H), 0.99 - 0.83 (m, 1H). Analytical HPLC (Method A): RT = 9.3 min, purity = 99.5%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 24 nM.

Example 125

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-11-fluoro-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( Preparation of 18),2(6),4,14,16-pentaen-8-one

Example 124A, tert-Butyl N-[(9R,13S)-3-(difluoromethyl)-11-fluoro-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3 The second eluting isomer from .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.034 g, 0.075 mmol) was purified in HCl. (4.0 M in dioxane) (0.376 ml, 1.50 mmol). A minimal amount of MeOH was added to assist dissolution. After 2 hours, the reaction mixture was concentrated to dryness. The residue was dissolved in MeOH and passed through a NaHCO ₃ cartridge (Stratosphere SPE; 500 mg, 0.90 mmol loading). The filtrate was concentrated and the free base was temporarily set aside. Separately, 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidine prepared as described in Intermediate 9 in ACN (1.120 ml) To a flask containing a white suspension of -4-ol (0.023 g, 0.075 mmol) was added HATU (0.031 g, 0.083 mmol) and DBU (0.015 ml, 0.098 mmol). After 20 minutes, free base (1 mL) in DMF was added and the resulting suspension was stirred at room temperature overnight. The reaction mixture was _subjected to reverse phase chromatography (Sunfire C18 5μ ₃₀ - 0.1% TFA) purified. The pure fraction was concentrated to remove most of the ACN and the remaining aqueous phase was freeze-dried to (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3 -triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-11-fluoro-9-methyl-3,4 ,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (8.9 mg, 18.2%) as a white solid It was obtained as. MS(ESI) m/z: 643 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.35 (s, 1H), 8.20 (s, 1H), 7.88 (d, J=2.5 Hz, 1H), 7.80 (s, 1H), 7.76 - 7.74 (m, 1H), 7.70 (s, 1H), 7.69 - 7.60 (m, 3H), 7.57 - 7.51 (m, 1H), 6.44 (d, J=0.8 Hz, 1H), 6.11 (dd, J=13.1, 2.9 Hz) , 1H), 4.55 - 4.40 (m, 1H), 2.96 - 2.83 (m, 1H), 2.76 - 2.69 (m, 1H), 2.47 - 2.38 (m, 1H), 2.21 - 2.12 (m, 1H), 2.03 - 1.92 (m, 1H), 1.26 (d, J=6.6 Hz, 3H). Analytical HPLC (Method A): 9.41 min, purity = 99.5%; Factor XIa Ki = 20 nM, plasma kallikrein Ki = 2,400 nM.

Example 126

(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-10,16-difluoro-3,9-dimethyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2 Preparation of (6),4,14,16-pentaen-8-one

126A. N-[(9S,13S)-10,16-difluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( Preparation of 18),2(6),4,14,16-pentaen-13-yl]carbamate

Fe ₂ (C ₂ O ₄ ) ₃ .6H ₂ O (2.16 g, 4.46 mmol) was added to RBF containing H ₂ O (30 ml). The suspension was warmed by water bath (50° C.) to aid dissolution. After 3 hours, the clear yellow solution was cooled to 0°C and purged with Ar. After 20 minutes, Selectfluor® (1.58 g, 4.46 mmol) in ACN (5 ml) was added followed by tert-butyl N-[(9R,10E, prepared as described in Intermediate 29D in ACN (10 ml) 13S)-16-Fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 ,10,14,16-hexaen-13-yl]carbamate (0.370 g, 0.893 mmol) was added dropwise. After 5 minutes, NaBH ₄ (0.270 g, 7.14 mmol) was added in two separate portions over a 5 minute period. After 15 minutes, the reaction mixture was allowed to warm to room temperature. After 1 hour, the reaction mixture was quenched with 28-30% aqueous NH ₄ OH (15 mL). After 30 minutes, the reaction mixture was filtered, the solid was washed with EtOAc, the organic portion was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a crude mixture of isomers. The material was subjected to chiral _purification using Chiralpak® IC, 21 The initially eluted isomer was purified with tert-butyl N-[(9S,13S)-10,16-difluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (99.5% ee; 68 mg, 17.50%) and the second eluting isomer tert-Butyl N-[(9R,13S)-11,16-difluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-13-yl]carbamate (99.5% ee; 32 mg, 8.3%). 435 (M+H) ⁺ .

126B. (9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-10,16-difluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2 Preparation of (6),4,14,16-pentaen-8-one

tert-Butyl N-[(9S,13S)-10,16-difluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca The initially eluted isomer assigned to -1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.034 g, 0.078 mmol) was purified in 4 M HCl in dioxane (0.391 ml, 1.570 mmol). A minimal amount of MeOH was added to assist dissolution. After 2 hours, the reaction mixture was concentrated to dryness. The residue was dissolved in MeOH and passed through a NaHCO ₃ cartridge (Stratosphere SPE; 500 mg, 0.90 mmol loading). The filtrate was concentrated and the free base was temporarily set aside. Separately, 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl) phenyl)pyrimidine prepared as described in Intermediate 9 in ACN (1.120 ml) To a flask containing a white suspension of -4-ol (0.024 g, 0.078 mmol) was added HATU (0.033 g, 0.086 mmol) and DBU (0.015 ml, 0.102 mmol). After 20 minutes, free base (1 mL) in DMF was added and the resulting suspension was stirred at room temperature overnight. The reaction mixture was _subjected to reverse phase chromatography (Sunfire C18 5μ ₃₀ - 0.1% TFA) purified. The pure fraction was concentrated to remove most of the ACN and the remaining aqueous phase was freeze-dried to (9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3 -triazol-1-yl) phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10,16-difluoro-3,9-dimethyl-3,4,7-tri Azatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (18.5 mg, 37.5%) was obtained as a white solid. MS(ESI) m/z: 643 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.81 (s, 1H), 8.39 (s, 1H), 7.94 (d, J=2.5 Hz, 1H), 7.80 - 7.76 (m, 1H), 7.72 - 7.68 ( m, 1H), 7.50 (s, 1H), 7.40 (s, 1H), 7.31 (dt, J=9.0, 1.8 Hz, 1H), 7.06 - 7.02 (m, 1H), 6.44 (s, 1H), 5.91 (dd, J=13.5, 4.4 Hz, 1H), 5.37 - 5.25 (m, 1H), 4.04 (s, 3H), 3.16 (ddd, J=11.3, 7.1, 3.9 Hz, 1H), 2.48 - 2.41 (m , 1H), 2.30 - 2.24 (m, 1H), 1.88 - 1.77 (m, 1H), 1.05 (d, J=6.9 Hz, 3H), 0.99 - 0.86 (m, 1H). Analytical HPLC (Method A): RT = 8.84 min, purity = 99.5%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 12 nM.

Example 127

(9S,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10,16-difluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 Preparation of (18),2(6),4,14,16-pentaen-8-one

tert-Butyl N-[(9S,13S)-10,16-difluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[ prepared as described in Example 126A 12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.034 g, 0.078 mmol) initially eluted isomer assigned was treated with HCl (4.0 M in dioxane) (0.391 ml, 1.570 mmol). A minimal amount of MeOH was added to assist dissolution. After 2 hours, the reaction mixture was concentrated to dryness. The residue was dissolved in MeOH and passed through a NaHCO ₃ cartridge (Stratosphere SPE; 500 mg, 0.90 mmol loading). The filtrate was concentrated and the free base was temporarily set aside. Separately, 6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl prepared as described in Intermediate 15 in ACN (1.120 ml) To a flask containing a white suspension of ]phenyl}pyrimidin-4-ol (0.027 g, 0.078 mmol) was added HATU (0.033 g, 0.086 mmol) and DBU (0.015 ml, 0.102 mmol). After 20 minutes, free base (1 mL) in DMF was added and the resulting suspension was stirred at room temperature overnight. The reaction mixture was _subjected to reverse phase chromatography (Sunfire C18 5μ ₃₀ -0.1% TFA) was purified. The pure fraction was liberated from the organic portion and the remaining aqueous phase was freeze-dried to obtain (9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazole). -1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-10,16-difluoro-3,9-dimethyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (23 mg, 44.2%) was obtained as a white solid. MS(ESI) m/z: 659.2 (M+H) ⁺ .

¹ H NMR (500 MHz, CD ₃ OD) δ 8.87 (d, J=0.8 Hz, 1H), 8.77 (s, 1H), 7.95 (d, J=2.2 Hz, 1H), 7.82 - 7.78 (m, 1H) , 7.76 - 7.71 (m, 1H), 7.50 (s, 1H), 7.39 (s, 1H), 7.33 - 7.28 (m, 1H), 6.99 (dt, J=9.3, 1.8 Hz, 1H), 6.51 (d) , J=0.8 Hz, 1H), 5.91 (dd, J=13.3, 4.5 Hz, 1H), 5.37 - 5.24 (m, 1H), 4.07 - 4.02 (m, 3H), 3.15 (ddd, J=11.5, 7.2 , 3.9 Hz, 1H), 2.42 (tt, J=13.2, 4.0 Hz, 1H), 2.23 (tt, J=13.0, 4.0 Hz, 1H), 1.85 - 1.78 (m, 1H), 1.05 (d, J= 6.9 Hz, 3H), 0.96 - 0.87 (m, 1H). Analytical HPLC (Method A): RT = 9.26 min, purity = 99.7%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 10 nM.

Example 128

(9R,13S)-13-{4-[5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo [ _12.3.1.0 ^2,6 ]octadeca-1(18),2 Preparation of (6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo[ _12.3.1.0 ^2,6 ] octadeca-1(18),2 (6),4,14,16-pentaen-8-one (1.68 mg, 15% yield) was obtained as (9R,13S)- prepared as described in Intermediate 33 in a manner similar to the procedure described in Example 167. 13-amino-3-( ^2H3 )methyl-9 _- methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6), Prepared using 4,14,16-pentaen-8-one (5.35 mg, 0.018 mmol). MS(ESI) m/z: 598.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.17 (s, 1H), 7.86 (s, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.75 (s, 1H), 7.68 (dd, J= 8.4, 2.4 Hz, 1H), 7.59 - 7.55 (m, 3H), 7.49 (s, 1H), 7.32 (d, J=7.3 Hz, 1H), 6.23 (s, 1H), 5.81 (dd, J=13.1 , 3.4 Hz, 1H), 2.53 - 2.26 (m, 2H), 2.13 - 1.80 (m, 3H), 1.63 - 1.49 (m, 2H), 1.27-1.09 (m, 4H), 1.01 - 0.91 (m, 2H) ), 0.78 - 0.69 (m, 2H). Analytical HPLC (Method A): RT = 8.15 min, purity = 95.3%; Factor XIa Ki = 2 nM, plasma kallikrein Ki = 280 nM

Example 129

6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S)-3-(di Fluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene Preparation of -13-yl]-3,4-dihydropyrimidin-4-one

6-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-3-[(9R,13S)-3-(di Fluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene -13-yl]-3,4-dihydropyrimidin-4-one was prepared as described in Intermediate 30 in a manner similar to the procedure described in Example 123 (9R,13S)-13-amino-3-( difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-penta Prepared using en-8-one.

¹ H NMR (400MHz, CD ₃ OD δ 8.99 (s, 1H), 8.73 (d, J=5.3 Hz, 1H), 8.32 (s, 1H), 8.30 (s, 1H), 7.86 (dd, J=8.6 , 7.7 Hz, 1H), 7.57 (s, 1H), 7.56 - 7.52 (m, 2H), 7.49 (d, J=5.1 Hz, 1H), 6.61 (s, 1H), 6.18 (dd, J=12.5, 5.1 Hz, 1H), 2.67 (d, J=11.7 Hz, 1H), 2.36 - 2.22 (m, 1H), 2.19 - 1.99 (m, 3H), 1.82 (br. s., 1H), 1.49 (br. s., 1H), 1.24 (m, 1H), 0.76 (d, J=7.3 Hz, 3H), 0.45 (br. s., 1H). MS(ESI) m/z: 630.2 (M+H) ⁺ Analytical HPLC (Method A): RT = 11.06 min, purity = 99.3%, factor XIa Ki = 0.8 nM, plasma kallikrein Ki = 880 nM.

Example 130

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18 ), 2(6),4,14,16-pentaene-16-carbonitrile production

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazole-) described in Example 84 in ACN (0.3 mL) cooled to 0°C. 1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triaza To tricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxamide (0.004 g, 5.98 μmol), several drops of pyridine was added, and then POCl ₃ (0.91 mg, 5.98 μmol) was added. After 2 hours, the reaction was concentrated and purified by preparative LCMS to give (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazole- 1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triaza Tricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-16-carboxamide (1.7 mg, 43%) was obtained as a white solid. . MS(ESI) m/z: 650.3 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.71 (s, 1H), 8.56 (s, 1H), 7.95 (d, J=1.4 Hz, 2H), 7.89 (t, J =2.9 Hz, 3H), 7.87 - 7.80 (m, 2H), 7.77 - 7.71 (m, 1H), 6.40 (s, 1H), 5.55 (d, J=10.5 Hz, 1H), 1.98 - 1.79 (m, 2H), 1.52 - 1.36 (m, 1H), 1.12 (br. s., 1H), 1.04 - 0.98 (m, 1H), 0.96 (d, J=6.9 Hz, 3H). Analytical HPLC (Method C) RT=1.76 min, purity=99%; Factor XIa Ki = 0.2 nM, plasma kallikrein Ki = 29 nM.

Example 131

(9R,13S)-13-(4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1, 6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) , Preparation of 4,14,16-pentaen-8-one trifluoroacetate

131A. Preparation of 6-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl} pyrimidin-4-ol, hydrobromide

4-{5-chloro-2-[4-(trimethylsilyl-1H-1,2,3-) prepared as described in Intermediate 9 in AcOH (0.75 ml) and 48% aqueous HBr (0.42 ml, 3.75 mmol) A clear yellow solution of [triazol-1-yl]phenyl}-6-methoxypyrimidine (0.027 g, 0.075 mmol) was warmed to 65° C. After 1.5 hours, the reaction was concentrated. MeOH was added and the reaction mixture This was repeated (2x) to give an 86:14 mixture of 6-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidine. -4-ol, hydrobromide and 6-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol, hydrobromide (0.0294 g, 92% Yield) was obtained as an off-white solid. MS(ESI) m/z: 346.0 (M+H) ⁺ .

131B. (9R,13S)-13-(4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1, 6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) , Preparation of 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1, 6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6) ,4,14,16-pentaen-8-one trifluoroacetate (0.0087 g, 16% yield) was purified from 6-{5-chloro-2-[4-( trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol hydrobromide and (9R,13S)-13-amino-3, prepared as described in Intermediate 32, 9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one It was manufactured using. MS(ESI) m/z: 628.4 (M+H) ⁺ and 630.5 (M+2+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.84 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.17 (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.72 (dd, J=8.6, 2.4 Hz, 1H), 7.66 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.51 (dd, J=5.2, 1.4 Hz, 1H), 7.48 (s, 1H), 6.13 (s, 1H), 5.98 (dd, J=12.7, 4.3 Hz, 1H), 4.04 (s, 3H), 2.74 - 2.66 (m, 1H), 2.32 - 2.21 (m, 1H), 2.12 - 1.90 (m, 2H), 1.66 - 1.53 (m, 1H), 1.53 - 1.39 (m, 1H), 0.99 (d, J=7.0 Hz, 3H), 0.73 - 0.58 (m, 1H), 0.29 (m) , 9H). ¹⁹ F NMR (376MHz, CD ₃ OD) δ -77.51 (br. s., 1F).

Analytical HPLC (Method X): RT = 6.62 min, purity = 93.5%; Factor XIa Ki = 29 nM, plasma kallikrein Ki = 760 nM.

Example 132

(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl- 3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one of trifluoroacetate manufacturing.

6-(3-chloro-2,6-difluorophenyl) pyrimidin-4-ol (0.013 g, 0.054 mmol) prepared as described in Intermediate 4 in ACN (0.54 ml), and HATU (0.027 g, DBU (0.012 ml, 0.081 mmol) was added to a 1-dram vial containing 0.070 mmol) of the white suspension. The resulting light yellow solution was stirred at room temperature for 20 minutes. Over time this solution became a dull yellow-orange color. Then, (9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, prepared as described in Intermediate 32 in DMF (0.54 ml) ⁶ ]Octadeca-1(18),2(6),4,14,16-pentaen-8-one, a clear brown color of 2 HCl (0.020 g, 0.054 mmol), and DBU (0.016 ml, 0.107 mmol) The solution was added. After 2.5 hours, the reaction was stopped. Purified by reverse phase chromatography (9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl] -3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8 -one trifluoroacetate (0.0152 g, 43% yield) was obtained as an off-white solid. MS(ESI) m/z: 525.1 (M+H) ⁺

¹ H NMR (500MHz, CD ₃ OD) δ 9.04 (s, 1H), 8.75 (d, J=5.0 Hz, 1H), 7.73 (s, 1H), 7.63 (ddd, J=9.1, 8.3, 5.5 Hz, 1H), 7.55 - 7.51 (m, 1H), 7.50 (s, 1H), 7.14 (td, J=9.1, 1.7 Hz, 1H), 6.66 (d, J=0.6 Hz, 1H), 6.10 - 6.02 (m , 1H), 4.05 (s, 3H), 2.76 - 2.68 (m, 1H), 2.37 (tt, J=12.8, 4.5 Hz, 1H), 2.15 - 2.04 (m, 2H), 1.68 - 1.58 (m, 1H) ), 1.56 - 1.45 (m, 1H), 1.02 (d, J=6.9 Hz, 3H), 0.80 - 0.65 (m, 1H). ¹⁹ F NMR (471MHz, CD ₃ OD) δ -77.53 (s), -114.79 (d, J=4.3 Hz), -115.50 (d, J=4.3 Hz). Analytical HPLC (Method A): RT = 7.37 min, purity = 99.7%; Factor XIa Ki = 33 nM, plasma kallikrein Ki = 290 nM.

Example 133

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidine- 1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16- Preparation of pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidine- 1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16- Pentaen-8-one trifluoroacetate (14 mg, 38% yield) was purified from 6-(3-chloro-2,6-difluorophenyl)pyrimidine-4 in a manner similar to the procedure described in Example 132. -ol was reacted with 6-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol (0.015 g, 0.054 mmol) prepared as described in Intermediate 8. ) was prepared by replacing it with . MS(ESI) m/z: 558.4 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.83 (s, 1H), 8.71 (d, J=5.0 Hz, 1H), 8.21 (s, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.84 (br. s., 1H), 7.72 (dd, J=8.4, 2.3 Hz, 1H), 7.67 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.51 (dd, J=5.1, 1.5 Hz, 1H), 7.48 (s, 1H), 6.18 (s, 1H), 6.00 - 5.93 (m, 1H), 4.04 (s, 3H), 2.73 - 2.66 (m, 1H), 2.31 - 2.23 (m) , 1H), 2.11 - 1.91 (m, 2H), 1.64 - 1.54 (m, 1H), 1.51 - 1.40 (m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.72 - 0.59 (m, 1H) ). ¹⁹ F NMR (471 MHz, CD ₃ OD) δ -77.37 (s). Analytical HPLC (Method A): RT = 6.22 min, purity = 99.2%; Factor XIa Ki = 1.8 nM, plasma kallikrein Ki = 110 nM.

Example 134

(13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 Preparation of 14,16-pentaen-8-one trifluoroacetate

134A. tert-Butyl N-[(1S)-1-{4-[4-(but-3-enamido)-1-(difluoromethyl)-1H-pyrazol-5-yl]pyridin-2- Preparation of }but-3-en-1-yl]carbamate

tert-Butyl N-[(1S)-1-{4-[4-amino-1-(difluoromethyl)-1H-pyrazole-5- prepared as described in Intermediate 30C in EtOAc (10.1 ml) yl]pyridin-2-yl}but-3-en-1-yl]carbamate (0.608 g, 1.60 mmol) was added to a cooled (-5°C) yellow solution of but-3-enoic acid (0.14 ml, 1.60 mmol). ) and pyridine (0.26 ml, 3.21 mmol) were added. Next, T3P® (50% in EtOAc, 1.43 ml, 2.40 mmol) was added dropwise. The resulting orange solution was allowed to warm to room temperature. After 2 hours, the reaction was diluted with EtOAc, washed with saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a yellow foam weighing 0.702 g. Purified by normal phase chromatography, tert-butyl N-[(1S)-1-{4-[4-(but-3-enamido)-1-(difluoromethyl)-1H-pyrazole-5 -yl]pyridin-2-yl}but-3-en-1-yl]carbamate (0.374 g, 52% yield) was obtained as a white foam. MS(ESI) m/z: 448.2 (M+H) ⁺ .

¹ H NMR (500 MHz, CD ₃ OD) δ 8.65 (d, J=4.7 Hz, 1H), 8.04 (s, 1H), 7.44 (s, 1H), 7.40 (t, J=58.0 Hz, 1H), 7.36 (d, J=4.4 Hz, 1H), 5.92 (ddt, J=17.1, 10.2, 7.0 Hz, 1H), 5.80 (ddt, J=17.2, 10.2, 6.9 Hz, 1H), 5.19 - 5.13 (m, 2H) ), 5.12 - 5.03 (m, 2H), 4.81 - 4.75 (m, 1H), 3.08 (d, J=6.9 Hz, 2H), 2.67 - 2.59 (m, 1H), 2.54 - 2.46 (m, 1H), 1.42 (s, 9H). ¹⁹ F NMR (471 MHz, CD ₃ OD) δ -93.82 (br. s).

134B. tert-Butyl N-[(10E,13S)-3-(difluoromethyl)-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( Preparation of 18),2(6),4,10,14,16-hexaen-13-yl]carbamate

tert-Butyl N-[(1S)-1-{4-[4-(but-3-enamido)-1-(difluoromethyl)-1H-pyrazole-5- in DCE (20.89 ml) A solution of yl]pyridin-2-yl}but-3-en-1-yl]carbamate (0.374 g, 0.836 mmol) was purged with Ar (3x). Second generation Grubbs catalyst (0.284 g, 0.334 mmol) was added to the reaction mixture. The microwave vial was sealed and the reaction was heated in the microwave at 115°C for 1 hour. The reaction was cooled to room temperature and concentrated. The residue was purified by normal phase chromatography to obtain tert-butyl N-[(10E,13S)-3-(difluoromethyl)-8-oxo-3,4,7,15-tetraazatricyclo[12.3. 1.0 ^2,6 ] octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.106 g, 30% yield) was obtained as a brown residue. did. MS(ESI) m/z: 420.1 (M+H) ⁺ .

134C. tert-Butyl N-[(13S)-3-(difluoromethyl)-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18) ,2(6),4,14,16-pentaen-13-yl]Manufacture of carbamate

tert-Butyl N-[(10E,13S)-3-(difluoromethyl)-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6) in EtOH (5.0 ml) A clear orange-brown solution of ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.105 g, 0.250 mmol) was incubated with Ar for several minutes. Purged. Next, 10% Pd/C (0.027 g, 0.025 mmol) was added and the suspension was pressurized to 55 psi using H ₂ gas. After 17 hours, Celite® was added. The reaction was filtered through a nylon filter, eluting with EtOH, to give a clear orange solution. The filtrate was concentrated to give a clear orange residue. Purification by reverse phase chromatography gave a white solid, after neutralization and concentration of the fractions with saturated NaHCO ₃ . The solid was partitioned between EtOAc and water and the layers were separated. The aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give tert-butyl N-[(13S)-3-(difluoromethyl)-8-oxo-3,4, 7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.0518 g, 49 % yield) was obtained as a white solid. MS(ESI) m/z: 422.1 (M+H) ⁺ .

134D. (13S)-13-amino-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6), Preparation of 4,14,16-pentaen-8-one, bis-hydrochloride

tert-Butyl N-[(13S)-3-(difluoromethyl)-8-oxo-3,4,7,15-tetraazatricyclo[ in 4 M HCl in dioxane (1.54 ml, 6.15 mmol) 12.3.1.0 A clear, colorless solution of ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.0518 g, 0.123 mmol) was prepared at room temperature. It was stirred. After 5 minutes, a white precipitate formed. After 1 hour, the reaction was concentrated to (13S)-13-amino-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-8-one, bis-hydrochloride (0.0503 g, 104% yield) was obtained as an off-white solid. MS(ESI) m/z: 322.1 (M+H) ⁺ .

¹ H NMR (500 MHz, CD ₃ OD) δ 8.82 (d, J=5.2 Hz, 1H), 7.72 (s, 1H), 7.59 (dd, J=60.0, 57.2 Hz, 1H), 7.58 (d, J= 5.2 Hz, 1H), 7.54 (s, 1H), 4.61 (dd, J=11.1, 5.1 Hz, 1H), 2.45 (ddd, J=12.6, 7.4, 2.3 Hz, 1H), 2.22 - 2.13 (m, 1H) ), 2.06 - 1.99 (m, 1H), 1.87 - 1.71 (m, 2H), 1.67 - 1.57 (m, 1H), 1.52 - 1.42 (m, 1H), 0.84 - 0.73 (m, 1H). ¹⁹ F NMR (471MHz, CD ₃ OD) δ -89.17 (d, J=228.9 Hz, 1F), -98.00 (d, J=227.5 Hz, 1F).

134E. (13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4 Preparation of 14,16-pentaen-8-one trifluoroacetate

6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidine-4- prepared as described in Intermediate 9 in ACN (0.51 ml) DBU (0.011 ml, 0.076 mmol) was added to a 1-dram vial containing a yellow suspension of OL (0.016 g, 0.051 mmol), and HATU (0.025 g, 0.066 mmol). The resulting yellow-orange solution was stirred at room temperature for 20 minutes. Over time the solution became a dull yellow-orange color. Then, (13S)-13-amino-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1( A clear yellow solution of 18),2(6),4,14,16-pentaen-8-one, bis-hydrochloride (0.020 g, 0.051 mmol) and DBU (0.015 ml, 0.101 mmol) was added. The reaction was stirred at room temperature. After 3 hours, the reaction was quenched with saturated NH ₄ Cl. The mixture was partitioned between EtOAc and water and the layers were separated. The aqueous layer was extracted with EtOAc (2x). The organic layers were combined, washed with saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a clear yellow residue weighing 0.040 g. Purified by reverse phase chromatography, (13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18) ,2(6),4,14,16-pentaen-8-one trifluoroacetate (0.0175 g, 47% yield) was obtained as a white solid. MS(ESI) m/z: 612.2 (M+H) ⁺ and 614.1 (M+2+H) ⁺ .

¹ H NMR (500MHz, DMSO-d6, 60℃) δ 9.28 (s, 1H), 8.78 (d, J=0.5 Hz, 1H), 8.72 (d, J=5.0 Hz, 1H), 8.64 (s, 1H) ), 7.91 (d, J=2.2 Hz, 1H), 7.89 (t, J=57.8 Hz, 1H), 7.86 (s, 1H), 7.81 - 7.78 (m, 1H), 7.72 (d, J=8.5 Hz) , 1H), 7.64 (d, J=0.6 Hz, 1H), 7.42 (dd, J=5.1, 1.2 Hz, 1H), 6.32 (d, J=0.8 Hz, 1H), 5.93 (dd, J=12.7, 4.4 Hz, 1H), 2.41 - 2.36 (m, 1H), 2.29 - 2.20 (m, 1H), 2.00 - 1.87 (m, 3H), 1.64 - 1.53 (m, 1H), 1.44 - 1.33 (m, 1H) , 0.76 - 0.66 (m, 1H). ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -73.75 (br. s), -90.34 (d, J=227.4 Hz), -95.01 (d, J=228.9 Hz). Analytical HPLC (Method A): RT = 7.78 min, purity = 99.8%.

Example 135

(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), Preparation of 2(6),4,14,16-pentaen-8-one

135A. tert-Butyl ((1S)-1-(4-(1-(difluoromethyl)-4-(2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2 Preparation of -1)but-3-en-1-yl)carbamate

(S)-tert-butyl (1-(4-(4-amino-1-(difluoromethyl)-1H-pyra prepared as described in Intermediate 30C) in 3-neck, 250 mL RBF, flushed with N ₂ A solution of sol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (1.8 g, 4.74 mmol), and EtOAc (20 mL) was added. Cool the solution to -10°C and add (±)-2-methylbut-3-enoic acid (0.475 g, 4.74 mmol), pyridine (0.767 mL, 9.49 mmol), and T3P® (4.24 mL, 7.12 mmol). did. The cooling bath was removed and the solution was allowed to warm to room temperature and then stirred over a period of 20 hours. Water (15 mL) and EtOAc (15 mL) were added and the mixture was stirred for 30 minutes. The organic phase was separated and the aqueous layer was extracted with EtOAc (30 mL). The combined organic extracts were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated. Purification by normal phase chromatography eluting with gradient hexane/EtOAc gave racemic tert-butyl ((1S)-1-(4-(1-(difluoromethyl)-4-(2-methylbut-3-ene Amido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (1.7 g, 3.50 mmol, 74% yield) was obtained. MS(ESI) m/z: 462.4 [M+H] ⁺ .

135B1. tert-Butyl N-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate, and 135B2. tert-Butyl N-[(9S,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]Octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]Preparation of carbamate

tert-butyl ((1S)-1-(4-(1-(difluoromethyl)-4-(2-methylbut-3) in EtOAc (175 mL) in ₅₀₀ mL, 3-neck RBF, N 2 flushed. A solution of -enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (1.7 g, 3.68 mmol) was added. The solution was aerated with Ar for 15 minutes. Second generation Grubbs catalyst (0.782 g, 0.921 mmol) was added in one portion. The reaction mixture was heated at reflux for 24 hours. After cooling to room temperature, the solvent is removed and the residue is purified by normal phase chromatography eluting with a gradient of DCM/MeOH to give (separated diastereomers) tert-butyl N-[(9R,10E,13S)- 3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,10,14,16-hexaen-13-yl]carbamate (0.33 g, 0.75 mmol, 20% yield) and tert-butyl N-[(9S,10E,13S)-3-(difluoro methyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14, 16-Hexaen-13-yl]carbamate (0.34 g, 0.77 mmol, 21% yield) was obtained as a tan solid. 2 diastereomers: MS(ESI) m/z: 434.3 [M+H] ⁺ .

135C. tert-Butyl N-[(9S,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

Pd/C (0.082 g, 0.078 mmol) was dissolved in tert-butyl N-[(9S,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3, 4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate ( was added to a 100 mL Parr hydrogenation flask containing a solution of 0.33 g, 0.775 mmol). The flask was purged with N ₂ , pressurized with 55 psi of H ₂ and allowed to stir for 5 hours. The reaction was filtered through Celite® and concentrated to give tert-butyl N-[(9S,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetra. Azatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.3 g, 0.654 mmol, 84% yield ) was obtained as a tan solid. MS(ESI) m/z: 436.3 [M+H] ⁺ .

135D. (9S,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of ,2(6),4,14,16-pentaen-8-one

4 N HCl in dioxane (5.00 mL, 20.0 mmol) was dissolved in tert-butyl N-[(9S,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3 in MeOH (5 mL). ,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (0.300 g, 0.689 mmol) was added to the solution. The reaction was allowed to stir at room temperature for 1 hour. The reaction was concentrated to (9S,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one bis-hydrochloride (0.24 g, 0.644 mmol, 93% yield) was obtained as a brown solid which was then washed with MeOH (1 mL ) to obtain a clear brown solution. The solution was added to a pre-rinsed Agilent® Stratosphere SPE PL-HCO ₃ MP resin cartridge. Gravity filtration eluting with MeOH gave a clear, slightly yellow filtrate. Concentrate to obtain (9S,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-8-one (0.18 g, 94%) was obtained as a light yellow solid. MS(ESI) m/z: 336.3 [M+H] ⁺ .

135E. (9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18), Preparation of 2(6),4,14,16-pentaen-8-one trifluoroacetate

(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), 2(6),4,14,16-pentaen-8-one trifluoroacetate was prepared as described in Intermediate 9 in a manner similar to the procedure described in Example 56, 6-(5-chloro-2- (4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (0.221 g, 0.716 mmol), and (9S,13S)-13-amino-3-( difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-penta (9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazole) prepared using en-8-one (0.021 g, 0.062 mmol) -1-yl) phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatri Cyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (0.16 g, 0.205 mmol, 29% yield) Obtained.

¹ H NMR (400MHz, CD ₃ OD) δ 8.85 (s, 1H), 8.75 (d, J=5.1 Hz, 1H), 8.37 (s, 1H), 7.93 (d, J=2.2 Hz, 1H), 7.85 - 7.75 (m, 3H), 7.72 - 7.67 (m, 1H), 7.62 (s, 1H), 7.57 - 7.48 (m, 1H), 6.43 (s, 1H), 6.08 (dd, J=12.9, 4.3 Hz , 1H), 2.41 - 2.30 (m, 1H), 2.29 - 2.17 (m, 1H), 2.09 - 1.90 (m, 2H), 1.68 - 1.52 (m, 2H), 1.28 (d, J=6.8 Hz, 3H) ), 0.93 - 0.81 (m, 1H). MS(ESI) m/z: 626.3 [M+H] ⁺ . Analytical HPLC (Method A): RT = 9.03 min, purity = >95.0%; Factor XIa Ki = 1.7 nM, plasma kallikrein Ki = 35 nM.

Example 136

(9R,13S)-13-{4-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), Preparation of 2(6),4,14,16-pentaen-8-one trifluoroacetate

136A. Preparation of 4-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine trifluoroacetate

Cooled (0° C.), clear yellow color of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (0.095 g, 0.403 mmol) prepared as described in Intermediate 8A in EtOH (5.0 ml). Hunig's base (0.42 ml, 2.42 mmol) was added to the solution. After 10 min, N'-[(2E)-1,1-dichloropropan-2-ylidene]-4-methylbenzene-1-sulfonohydrazide (0.242 g, 0.52 mmol) in ACN (3.3 ml) The suspension was added dropwise. The resulting orange solution was allowed to warm to room temperature. After 23 hours, the reaction was stopped and concentrated to give a dark brown oil. After purification and concentration by reverse phase chromatography, 4-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine trifluoride Roacetate (0.0499 g, 30% yield) was obtained as a clear yellow oil. MS(ESI) m/z: 302.1 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.64 (d, J=1.1 Hz, 1H), 7.88 (d, J=0.8 Hz, 1H), 7.85 (d, J=2.2 Hz, 1H), 7.73 (dd , J=8.5, 2.2 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 6.59 (d, J=1.1 Hz, 1H), 3.97 (s, 3H), 2.33 (d, J=0.8 Hz) , 3H).

136B. Preparation of 6-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol

4-(5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl)- in AcOH (1.20 ml) and 48% aqueous HBr (0.68 ml, 6.00 mmol) A clear yellow solution of 6-methoxypyrimidine, TFA (0.0499 g, 0.12 mmol) was warmed to 85°C. After 1 hour, the reaction was cooled to room temperature and then concentrated to give a yellow solid. The yellow solid was suspended in EtOAc and saturated NaHCO ₃ was added. The layers were separated and the aqueous layer was extracted with EtOAc (2x). The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give an off-white solid weighing 0.032 g. The solid was suspended in EtOAc (1 mL) and sonicated. The solid was collected by filtration, rinsed with EtOAc, air-dried, and dried under vacuum to give 6-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl). Phenyl]pyrimidin-4-ol (0.0144 g, 40% yield) was obtained as an off-white solid. MS(ESI) m/z: 288.1 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.07 (s, 1H), 7.92 (s, 1H), 7.84 (d, J=2.2 Hz, 1H), 7.71 (dd, J=8.5, 2.5 Hz, 1H) , 7.60 (d, J=8.5 Hz, 1H), 6.22 (s, 1H), 2.36 (s, 3H).

136C. (9R,13S)-13-{4-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18), Preparation of 2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), 2(6),4,14,16-pentaen-8-one trifluoroacetate (0.0070 g, 32% yield) was purified from 6-[5-chloro-2- in a manner similar to the procedure described in Example 56. (4-methyl-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol and (9R,13S)-13-amino-3-(difluoro) prepared in Intermediate 30 Methyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8 It was prepared using -on. MS(ESI) m/z: 606.3 (M+H) ⁺ and 608.2 (M+2+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.91 (s, 1H), 8.73 (d, J=5.2 Hz, 1H), 7.91 (d, J=0.8 Hz, 1H), 7.88 (d, J=2.5 Hz) , 1H), 7.73 (s, 1H), 7.70 (dd, J=8.5, 2.5 Hz, 1H), 7.68 - 7.67 (m, 1H), 7.65 (t, J=60.0 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.53 - 7.51 (m, 1H), 6.18 (d, J=0.8 Hz, 1H), 6.02 - 5.97 (m, 1H), 2.74 - 2.66 (m, 1H), 2.35 - 2.24 (m, 4H), 2.08 - 1.94 (m, 2H), 1.63 - 1.53 (m, 1H), 1.53 - 1.42 (m, 1H), 0.99 (d, J=6.9 Hz, 3H), 0.67 - 0.52 (m , 1H). ¹⁹ F NMR (471 MHz, CD ₃ OD) δ -74.24 (s), -75.74 (s), -77.66 (s). Analytical HPLC (Method A): RT = 7.55 min, purity = 99.8%; Factor XIa Ki = 2.2 nM, plasma kallikrein Ki = 630 nM.

Example 137

(9R,13S)-3-(difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethyl)-1H-1,2,3-tria zol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-3-(difluoromethyl)-9-methyl-13-(4-{5-methyl-2-[4-(trifluoromethyl)-1H-1,2,3-tria zol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (11 mg, 24%) was prepared as described in Example 119D in a similar manner to Example 56. 6-(5-methyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol and as described in Intermediate 30 Prepared (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1( It was prepared using 18),2(6),4,14,16-pentaen-8-one. MS(ESI) m/z: 640.2 (M+H) ⁺ .

^1H NMR (400MHz, CD ₃ OD) d 8.85 - 8.74 (m, 3H), 7.84 - 7.67 (m, 4H), 7.59 - 7.53 (m, 3H), 6.47 (s, 1H), 6.05 (dd, J =12.8, 4.4 Hz, 1H), 2.75 (dd, J=6.7, 3.0 Hz, 1H), 2.56 (s, 3H), 2.35 - 2.27 (m, 1H), 2.10 - 1.99 (m, 2H), 1.64 - 1.50 (m, 2H), 1.03 (d, J=6.8 Hz, 3H), 0.65 (br. s., 1H) Analytical HPLC (Method A): RT = 8.85 min, purity = 99%; Factor XIa Ki = 0.32 nM, plasma kallikrein Ki = 132 nM.

Example 138

(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4 Preparation of 7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4 ,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (160 mg, 46.8% yield) of 6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3 prepared as described in Intermediate 15 in a manner similar to the procedure described in Example 56. -Triazol-1-yl]phenyl}pyrimidin-4-ol (22.8 mg, 0.067 mmol) was reacted with 6-(2-bromo-5-chlorophenyl)pyrimidine-4- prepared as described in Intermediate 44. It was prepared by replacing it with all (143 mg, 0.501 mmol). MS(ESI) m/z: 567.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.04 (s, 1H), 8.75 (d, J=5.3 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.61 - 7.54 (m, 2H), 7.50 (s, 1H), 7.38 (dd, J=8.6, 2.4 Hz, 1H), 6.70 (s, 1H), 6.05 (dd, J=12.5, 4.0 Hz, 1H), 4.05 (s, 3H), 2.78 - 2.66 (m, 1H), 2.44 - 2.33 (m, 1H), 2.16 - 2.03 (m, 2H), 1.70 - 1.43 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.82 - 0.66 (m, 1H). Analytical HPLC (Method A): RT = 8.45 min, 99.9% purity; Factor XIa Ki = 23 nM, plasma kallikrein Ki = 420 nM.

Example 139

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one (0.0174 g, 62% yield) was purified from 6-[ described in Example 137B in a manner similar to the procedure described in Example 56. 3-chloro-2-fluoro-6-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol, and (prepared as described in Intermediate 30 9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18), Prepared using 2(6),4,14,16-pentaen-8-one. MS(ESI) m/z: 624.3 (M+H) ⁺ and 626.2 (M+2+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 9.52 (s, 1H), 8.90 (s, 1H), 8.75 (d, J=5.2 Hz, 1H), 7.89 (d, J=0.8 Hz, 1H), 7.82 (dd, J=8.7, 7.6 Hz, 1H), 7.74 (d, J=0.8 Hz, 1H), 7.69 (br. s, 1H), 7.65 (t, J=58.0 Hz, 1H), 7.53 - 7.49 ( m, 2H), 6.52 (s, 1H), 6.05 - 5.99 (m, 1H), 2.77 - 2.66 (m, 1H), 2.34 - 2.23 (m, 4H), 2.09 - 1.95 (m, 2H), 1.64 - 1.53 (m, 1H), 1.53 - 1.42 (m, 1H), 0.99 (d, J=7.2 Hz, 3H), 0.69 - 0.53 (m, 1H). ¹⁹ F NMR (471 MHz, CD ₃ OD) δ -74.25 (s), -75.75 (s), -115.22 (s). Analytical HPLC (Method A): RT = 7.54 min, purity = 99.8%; Factor XIa Ki = 0.63 nM, plasma kallikrein Ki = 119 nM.

Example 140

(9R,13S)-13-(4-{5-chloro-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydro Pyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14 , Preparation of 16-pentaen-8-one

140A. Preparation of 4-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-6-methoxypyrimidine

4-(2-bromo-5-chlorophenyl)-6-methoxypyrimidine (0.08 g, 0.267 mmol), 1-(difluoromethyl)-4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.072 g, 0.294 mmol), 3 M aqueous KH ₂ PO ₄ (0.27 ml, 0.81 mmol) and THF ( 2.67 ml) was added. Ar was bubbled through the reaction mixture for a few minutes and (DtBPF)PdCl ₂ (8.70 mg, 0.013 mmol) was added. The vial was sealed and heated at 90°C for 15 hours. The reaction was cooled to room temperature, diluted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purified by normal phase chromatography, 4-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-6-methoxypyrimidine (0.05 g, 56% Yield) was obtained as a white solid. MS(ESI) m/z: 337.2 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.81 (d, J=0.9 Hz, 1H), 7.69 (s, 1H), 7.54 (d, J=2.2 Hz, 1H), 7.48 - 7.43 (m, 1H), 7.41 - 7.35 (m, 2H), 7.17 (t, J=54.0 Hz, 1H), 6.61 (d, J=1.1 Hz, 1H), 3.99 (s, 3H).

140B. Preparation of 6-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)pyrimidin-4-ol

4-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-6 in HOAc (0.742 ml) and 48% aqueous HBr (0.84 ml, 7.42 mmol) A clear solution of -methoxypyrimidine (0.05 g, 0.148 mmol) was warmed to 65°C. After 3 hours, the reaction was cooled to room temperature and concentrated. The residue was dissolved in EtOAc, washed with saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated. Et ₂ O (3 ml) was added and the mixture was sonicated. The solid was collected by filtration, rinsed with Et ₂ O (2 ml) and air-dried to give 6-(5-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl) Phenyl)pyrimidin-4-ol (0.03 g, 63% yield) was obtained as a white solid. MS(ESI) m/z: 323.2 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.20 (d, J=1.1 Hz, 1H), 8.05 (s, 1H), 7.61 - 7.27 (m, 5H), 6.40 (d, J=1.1 Hz, 1H) .

140C. (9R,13S)-13-(4-{5-chloro-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydro Pyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14 , Preparation of 16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{5-chloro-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydro Pyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14 ,16-pentaen-8-one trifluoroacetate (10 mg, 32% yield) was purified from 6-(5-chloro-2-(1-(difluoromethyl) in a manner similar to the procedure described in Example 56. )-1H-pyrazol-4-yl)phenyl)pyrimidin-4-ol (14.01 mg, 0.043 mmol). MS(ESI) m/z: 605.2 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.95 (s, 1H), 8.74 (d, J=5.3 Hz, 1H), 8.04 (s, 1H), 7.72 (s, 1H), 7.60 - 7.25 (m, 7H), 6.42 (s, 1H), 6.02 (dd, J=12.7, 4.3 Hz, 1H), 4.05 (s, 3H), 2.76 - 2.66 (m, 1H), 2.39 - 2.27 (m, 1H), 2.14 - 1.99 (m, 2H), 1.67 - 1.42 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.81 - 0.65 (m, 1H). Analytical HPLC (Method A): RT = 8.18 min, 98.5% purity; Factor XIa Ki = 9 nM, plasma kallikrein Ki = 910 nM.

Example 141

(9R,13S)-13-[4-(3-fluoro-4-methylpyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl Preparation of -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

141A. Preparation of 4-methoxy-6-(tributylstannyl)pyrimidine

To RBF, 4-chloro-6-methoxypyrimidine (3.15 g, 21.79 mmol), 1,1,1,2,2,2-hexabutyldistannane (10.92 mL, 21.79 mmol), toluene (50 mL) and Pd(PPh ₃ ) ₄ (1.259 g, 1.090 mmol) were added. The reaction was purged with Ar and then stirred at 120°C overnight. The reaction was then partitioned between EtOAc (30 ml) and water (25 ml). The organic layer was separated, washed with saturated NaCl (20 ml), dried over MgSO ₄ , filtered and concentrated. The crude product was purified using the ISCO system (0-30% EtOAc/Hex gradient) to give 4-methoxy-6-(tributylstannyl)pyrimidine (200 mg, 0.501 mmol, 2.3% yield) as a clear liquid. It was obtained as.

^1H NMR (400MHz, CDCl ₃ ) δ 8.85 (d, J=1.1 Hz, 1H), 6.94 (d, J=1.1 Hz, 1H), 3.97 (s, 3H), 1.60 - 1.55 (m, 6H), 1.36 - 1.32 (m, 6H), 1.20 - 1.13 (m, 6H), 0.96 - 0.91 (m, 9H); MS(ESI) m/z: 401.1 (M+H) ⁺ .

141B. Preparation of 4-(3-fluoro-4-methylpyridin-2-yl)-6-methoxypyrimidine trifluoroacetate

2-Bromo-3-fluoro-4-methylpyridine (25.7 mg, 0.135 mmol), 4-methoxy-6-(tributylstannyl)pyrimidine (45 mg, 0.113 mmol), and toluene in a sealed tube. (1.5 mL) and Pd(PPh ₃ ) ₄ (13.03 mg, 0.011 mmol) were added. The reaction was purged with Ar, then sealed and stirred at 120°C overnight. The reaction was partitioned between EtOAc (25 ml) and water (20 ml). The organic layer was separated, washed with saturated NaCl (10 ml), dried over MgSO ₄ , filtered and concentrated. The crude product was purified using preparative HPLC to produce 4-(3-fluoro-4-methylpyridin-2-yl)-6-methoxypyrimidine trifluoroacetate (20 mg, 0.060 mmol, 53.2% yield). was obtained as a purple salt.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.22 (s, 1H), 8.59 (d, J=4.2 Hz, 1H), 7.56 (s, 1H), 7.51 (br. s., 1H), 4.23 (s, 3H), 2.51 (s, 3H); MS(ESI) m/z: 220.1 (M+H) ⁺ .

141C. Preparation of 6-(3-fluoro-4-methylpyridin-2-yl)pyrimidin-4-ol

Add 4-(3-fluoro-4-methylpyridin-2-yl)-6-methoxypyrimidine (20 mg, 0.060 mmol), AcOH (0.5 mL) and HBr (0.34 mL, 3.00 mmol) to RBF. did. The reaction was stirred at 85°C for 45 minutes. Toluene (25 ml) was then added and the reaction was concentrated. The residue was then partitioned between EtOAc (25 ml) and saturated NaHCO ₃ (25 ml). The organic layer was separated, washed with water (15 ml) and saturated NaCl (15 ml), dried over MgSO ₄ , filtered and concentrated to give 6-(3-fluoro-4-methylpyridin-2-yl) Pyrimidin-4-ol (10 mg, 0.049 mmol, 81% yield) was obtained as an oil. MS(ESI) m/z: 206.1 (M+H) ⁺ .

141D. (9R,13S)-13-[4-(3-fluoro-4-methylpyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate manufacture of

(9R,13S)-13-[4-(3-fluoro-4-methylpyridin-2-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (14 mg, 22 μmol, 41.4% yield) was purified from 6-(3-fluoro-4-methylpyridin-2-yl)pyrimidin-4-ol (15.3 mg, 0.053%) in a manner similar to the procedure described in Example 56. mmol) and (9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- prepared as described in Intermediate 32. It was prepared using 1(18),2(6),4,14,16-pentaen-8-one (16 mg, 0.053 mmol).

¹ H NMR (400MHz, CD ₃ OD) δ 9.21 (br. s., 1H), 8.76 (d, J=4.4 Hz, 1H), 8.49 (br. s., 1H), 7.77 (s, 1H), 7.66 (br. s., 1H), 7.56 (d, J=3.7 Hz, 1H), 7.52 (s, 1H), 7.15 (br. s., 1H), 6.10 (d, J=9.9 Hz, 1H) , 4.07 (s, 3H), 2.74 (d, J=12.3 Hz, 1H), 2.51 (br. s., 3H), 2.40 (br. s., 1H), 2.13 (br. s., 2H), 1.66 (br. s., 1H), 1.54 (br. s., 1H), 1.04 (d, J=6.8 Hz, 3H), 0.75 (br. s., 1H); MS(ESI) m/z: 488.2 (M+H) ⁺ . Analytical HPLC (Method A): RT = 6.97 min, purity = 97.0%; Factor XIa Ki = 110 nM, plasma kallikrein Ki = 2,200 nM.

Example 142

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18), Preparation of 2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), 2(6),4,14,16-pentaen-8-one trifluoroacetate (14.2 mg, 24%) was prepared as described in Intermediate 9 in a manner similar to Example 56. -2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol and (9R,13S)-13-amino- prepared as described in Intermediate 37 3-(difluoromethyl)-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14, Prepared using 16-pentaen-8-one. MS(ESI) m/z: 626.1 (M+H) ⁺ and 628.1 (M+2+H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.62 (d, J=5.1 Hz, 1H), 8.35 - 8.13 (m, 3H), 7.85 (s, 2H), 7.71 - 7.62 (m, 2H), 7.57 - 7.53 (m, 1H), 7.09 - 7.03 (m, 1H), 6.36 - 6.30 (m, 1H), 5.67 - 5.63 (m, 1H), 2.59 - 2.54 (m, 1H), 2.31 - 2.24 (m, 1H) , 2.04 - 1.94 (m, 2H), 1.59 - 1.54 (m, 1H), 1.30 - 1.21 (m, 2H), 1.03 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A): RT = 8.54 min, purity = 99%; Factor XIa Ki = 0.4 nM, plasma kallikrein Ki = 90 nM.

Example 143

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4, Preparation of 14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, 14,16-pentaen-8-one trifluoroacetate (9.7 mg, 21% yield) was purified from 6-{5-chloro-2-[4-(trifluoromethyl) in a manner similar to the procedure described in Example 56. )-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol was reacted with 6-[5-chloro-2-(4-chloro-1H-) prepared as described in Intermediate 9. It was prepared by replacing with 1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol (20 mg, 0.065 mmol). MS(ESI) m/z: 590.1 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.82 (s, 1H), 8.72 (d, J=5.0 Hz, 1H), 8.33 (s, 1H), 7.88 (d, J=2.5 Hz, 1H), 7.73 (dd, J=8.5, 2.2 Hz, 1H), 7.68 (s, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.52 - 7.49 (m, 1H), 7.49 (s, 1H), 6.36 ( s, 1H), 5.98 (dd, J=12.5, 3.7 Hz, 1H), 4.04 (s, 3H), 2.70 (td, J=6.5, 3.0 Hz, 1H), 2.33 - 2.24 (m, 1H), 2.12 - 1.95 (m, 2H), 1.65 - 1.55 (m, 1H), 1.52 - 1.42 (m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.74 - 0.61 (m, 1H). Analytical HPLC (Method A): RT = 11.54 min, purity = 99%; Factor XIa Ki = 0.17 nM, plasma kallikrein Ki = 20 nM.

Example 144

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2( 6),4,14,16-pentaen-8-one trifluoroacetate (9.9 mg, 22% yield) was prepared as described in Intermediate 10 in a manner similar to the procedure described in Example 56. -Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]prepared using pyrimidin-4-ol (20 mg, 0.061 mmol) . MS(ESI) m/z: 608.1 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.83 (s, 1H), 8.73 (d, J=5.2 Hz, 1H), 8.32 (s, 1H), 7.85 (dd, J=8.5, 7.7 Hz, 1H) , 7.68 (s, 1H), 7.55 (dd, J=8.7, 1.5 Hz, 1H), 7.51 (dd, J=5.2, 1.7 Hz, 1H), 7.49 (s, 1H), 6.60 (s, 1H), 6.00 (dd, J=12.8, 4.0 Hz, 1H), 4.05 (s, 3H), 2.75 - 2.64 (m, 1H), 2.29 (t, J=12.9 Hz, 1H), 2.14 - 1.95 (m, 2H) , 1.67 - 1.55 (m, 1H), 1.52 - 1.40 (m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.67 (m., 1H). ¹⁹ F NMR (471 MHz, CD ₃ OD) δ -76.98 (s), -115.06 (s). Analytical HPLC (Method A): RT = 11.58 min, purity = 98.5%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 6 nM.

Example 145

(9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4 Preparation of 14,16-pentaen-8-one trifluoroacetate

145A. Preparation of 4-[5-chloro-2-(4-bromo-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine

4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-methoxypyrimidine (114 mg, 56.0% yield) was prepared as intermediate 9D. Similar to the procedure described for the preparation of 4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine as described in It was prepared by replacing NCS with NBS (346 mg, 1.945 mmol). MS(ESI) m/z: 368.3 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.69 (d, J=0.9 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.66 (s, 1H), 7.61 (dd, J=8.5, 2.3 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 6.52 (d, J=1.1 Hz, 1H), 3.98 (s, 3H).

145B. Preparation of 6-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]pyrimidin-4-ol

6-[2-(4-Bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]pyrimidin-4-ol (47 mg, 42.9% yield) was added to intermediate 9E. In a manner similar to the procedure described, 4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine was reacted with 4-[2 Prepared by replacing -(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-methoxypyrimidine (114 mg, 0.311 mmol). MS(ESI) m/z: 354.2 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.01 (s, 1H), 7.76 (s, 1H), 7.73 (d, J=2.2 Hz, 1H), 7.62 (dd, J=8.5, 2.1 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 6.42 (s, 1H).

145C. (9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 Preparation of 14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[2-(4-bromo-1H-1,2,3-triazol-1-yl)-5-chlorophenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 , 14,16-pentaen-8-one trifluoroacetate (18.7 mg, 36.3% yield) was purified from 6-[2-(4-bromo-1H-1, It was prepared using 2,3-triazol-1-yl)-5-chlorophenyl]pyrimidin-4-ol (23.6 mg, 0.067 mmol). MS(ESI) m/z: 636.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.80 (s, 1H), 8.73 (d, J=5.3 Hz, 1H), 8.37 (s, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.75 - 7.68 (m, 2H), 7.65 - 7.60 (m, 1H), 7.53 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.35 (s, 1H), 5.97 (dd, J =12.7, 4.3 Hz, 1H), 4.05 (s, 3H), 2.75 - 2.65 (m, 1H), 2.35 - 2.22 (m, 1H), 2.12 - 1.95 (m, 2H), 1.66 - 1.53 (m, 1H) ), 1.51 - 1.38 (m, 1H), 1.00 (d, J=7.0 Hz, 3H), 0.77 - 0.60 (m, 1H). Analytical HPLC (Method A): RT = 10.12 min, purity = 96.9%; Factor XIa Ki = 0.13 nM, plasma kallikrein Ki = 18 nM.

Examples 146 and 147

1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1, 2,3-triazole-4-carboxamide trifluoroacetate, and

1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octa Deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1, Preparation of 2,3-triazole-4-carbonitrile trifluoro acetate

146A. Preparation of 1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide, and

147A. Preparation of 1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile

1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4 prepared as described in Intermediate 18A in DCM (1 mL) To a suspension of -carboxamide (150 mg, 0.45 mmol) was added TFAA (0.3 mL, 2.12 mmol) at room temperature, and the reaction was stirred for 1 hour. The reaction was concentrated to dryness, partitioned between saturated NaHCO ₃ and EtOAc and the layers separated. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were concentrated and then purified by normal phase chromatography to give 1-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole- Obtained 4-carboxamide (80 mg, 53.3% yield, MS(ESI) m/z: 331.3 (M+H) ⁺ ); 1-(4-Chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide (60.5 mg, 21.3% yield, MS( ESI) m/z: 331.3) was obtained, which was used as is in the subsequent step.

146B. Preparation of 1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide, and

147B. Preparation of 1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile

1-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbonitrile and 1-(4) in ACN (1 mL) Suspension of a 1:1 mixture of -chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide (60.5 mg, 0.194 mmol) TMSI (12 μL, 0.88 mmol) was added, and the solution was heated at 50° C. overnight. The reaction was poured into 10% aqueous Na ₂ S ₂ O ₃ and extracted with EtOAc (3x). The combined organic layers were concentrated to dryness and then suspended in DCM. The insoluble yellow solid was filtered to obtain 1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide and 1-[ A 5:3 mixture (15 mg) of 4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile was obtained, which It was used as is in subsequent steps. MS(ESI) m/z: 317.3, 299.3 (M+H) ⁺ . The filtrate was concentrated and then purified by normal phase chromatography to obtain 1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4. -Carbonitrile (20 mg, 34.6% yield) was obtained as a yellow solid. MS(ESI) m/z: 299.3

^1H NMR (400MHz, CDCl ₃ ) δ 8.23 (s, 1H), 7.93 (s, 1H), 7.73 (d, J=2.2 Hz, 1H), 7.66 (dd, J=8.4, 2.2 Hz, 1H), It was obtained as 7.49 (d, J=8.4 Hz, 1H), 6.54 (s, 1H).

146C. 1-(4-chloro-2-{1[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1,2 , Preparation of 3-triazole-4-carboxamide trifluoroacetate, and

147C. 1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1, Preparation of 2,3-triazole-4-carbonitrile trifluoroacetate

1-(4-Chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbonitrile and 1-[4 in ACN (1 mL) A scintillation vial containing a mixture of -chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboxamide (15 mg, 0.050 mmol) HATU (24.8 mg, 0.065 mmol) and DBU (11 μL, 0.075 mmol) were added. After 20 min, (9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraaza prepared as described in Intermediate 32 in ACN (0.5 ml) and DMF (0.1 ml) A solution of tricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-8-one (18.4 mg, 0.061 mmol) was added. The resulting solution was stirred at room temperature for 2 hours and then purified by reverse phase chromatography to obtain two products. 1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1, 2,3-triazole-4-carboxamide trifluoroacetate (3.8 mg, 10.5% yield) was obtained as a white solid. MS(ESI) m/z: 599.4 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.79 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.56 (s, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.76 - 7.71 (m, 1H), 7.69 - 7.64 (m, 2H), 7.51 (dd, J=5.2, 1.4 Hz, 1H), 7.48 (s, 1H), 6.35 (s, 1H), 5.96 (dd, J =12.8, 4.2 Hz, 1H), 4.04 (s, 3H), 2.75 - 2.63 (m, 1H), 2.33 - 2.21 (m, 1H), 2.12 - 1.92 (m, 2H), 1.66 - 1.53 (m, 1H) ), 1.52 - 1.40 (m, 1H), 1.00 (d, J=6.8 Hz, 3H), 0.74 - 0.60 (m, 1H). Analytical HPLC (Method A): RT = 8.06 min, purity = 98.4%; Factor XIa Ki = 0.44 nM, plasma kallikrein Ki = 99 nM.

1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-1, 2,3-triazole-4-carbonitrile trifluoroacetate (1.7 mg, 4.9% yield) was obtained as a white solid. MS(ESI) m/z: 581.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.93 (s, 1H), 8.73 (d, J=4.6 Hz, 2H), 7.90 (d, J=2.4 Hz, 1H), 7.79 - 7.73 (m, 1H) , 7.71 - 7.67 (m, 2H), 7.51 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.46 (d, J=0.7 Hz, 1H), 5.97 (dd, J=12.7 , 4.1 Hz, 1H), 4.05 (s, 3H), 2.70 (m, 1H), 2.34 - 2.21 (m, 1H), 2.13 - 1.94 (m, 2H), 1.67 - 1.53 (m, 1H), 1.52 - 1.39 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.71 (m, 1H). Analytical HPLC (Method A): RT = 10.08 min, purity = 99.2%; Factor XIa Ki = 0.11 nM, plasma kallikrein Ki = 20 nM.

Example 148

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2(7) ,Manufacture of 3,5,15,17-hexaene-5-carbonitrile

148A. tert-Butyl N-[(10R,14S)-5-bromo-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2 Preparation of (7),3,5,15,17-hexaen-14-yl]carbamate

tert-Butyl N-[(10R,14S)-5-bromo-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2 (7),3,5,15,17-hexaen-14-yl]carbamate was reacted with 2-bromo-5-methoxypyridin-3-amine in a manner similar to Example 81C to 2,5-diamine. Prepared by substitution with bromopyridin-3-amine (0.1 g, 49% yield, dark solid). LCMS (M+H) ⁺ 474-476.08.

148B. tert-Butyl N-[(10R,14S)-5-cyano-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2 Preparation of (7),3,5,15,17-hexaen-14-yl]carbamate

tert-Butyl N-[(10R,14S)-5-bromo-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1 in a microwave tube. (19),2(7),3,5,15,17-hexaen-14-yl]carbamate (0.1 g, 0.211 mmol), Zn(CN) ₂ (0.037 g, 0.316 mmol), Zn ( 4.13 mg, 0.063 mmol) and DMF (2.1 ml) were added. The mixture was purged with Ar for several minutes. Pd(t-Bu ₃ P) ₂ (10.77 mg, 0.021 mmol) was added. The reaction was sealed and heated at 80° C. for 18 hours. The reaction was partitioned using water (10 ml) and EtOAc (30 ml). The aqueous layer was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by phase chromatography using 10% MeOH in 100% DCM as eluent to give tert-butyl N-[(10R,14S)-5-cyano-10-methyl-9-oxo-3,8-dia. Zatricyclo[13.3.1.0 ^2, 7]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate (20 mg, 22.56% yield) was obtained. LCMS (M+H) ⁺ 421.3.

148C. (10R,14S)-14-amino-10-methyl-9-oxo-3,8-diazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5 , Production of 15,17-hexaene-5-carbonitrile

tert-Butyl N-[(10R,14S)-5-cyano-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2 (7),3,5,15,17-hexaen-14-yl]carbamate (0.02 g, 0.048 mmol), Example 148B was deprotected and the free base was produced in a similar manner to Example 81D. (10R,14S)-14-amino-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2(7),3, 5,15,17-hexaene-5-carbonitrile (13 mg, 85%) was obtained as a tan solid. LCMS (M+H) ⁺ 321.3.

148D. (10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10-methyl-9-oxo-3,8-diazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7) ,Manufacture of 3,5,15,17-hexaene-5-carbonitrile

6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol described in Intermediate 15 in a small vial (0.014 g, 0.041 mmol) and HATU (0.020 g, 0.053 mmol) were added DBU (9.17 μl, 0.061 mmol) in ACN (0.2 mL). After 30 minutes, (10R,14S)-14-amino-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7) ,3,5,15,17-hexaene-5-carbonitrile was added in DMF (0.4 ml). After 18 hours, the reaction was diluted with DMF, filtered and concentrated. The residue was purified by reverse phase HPLC using Phenomenex® Luna 5U 30x100 mm (10:90 ACN/H ₂ O to 90:10 ACN/H ₂ O, 0.1% TFA) (20% B starting, 14 min gradient). Purify (10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6- Oxo-1,6-dihydropyrimidin-1-yl)-10-methyl-9-oxo-3,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2( 7),3,5,15,17-hexaene-5-carbonitrile (4.9 mg, 14%) was obtained as a white solid. MS(ESI) m/z: 645.4 (M+H) ⁺ .

^1H NMR (400MHz, CD ₃ OD) δ 8.98 - 8.94 (m, 1H), 8.80 (s, 1H), 8.30 - 8.24 (m, 1H), 8.18 - 8.13 (m, 1H), 7.96 - 7.91 (m , 1H), 7.81 - 7.76 (m, 2H), 7.74 - 7.68 (m, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.32 (s, 1H), 6.49 - 6.46 (m, 1H), 5.81 (dd, J=12.7, 3.4 Hz, 1H), 2.56 (d, J=7.0 Hz, 1H), 2.31 (d, J=5.1 Hz, 1H), 2.16 - 2.08 (m, 1H), 1.93 (d , J=7.3 Hz, 1H), 1.58 (d, J=7.3 Hz, 1H), 1.46 (d, J=6.8 Hz, 1H), 1.37 (br. s., 1H), 1.26 - 1.21 (m, 1H) ), 1.17 (s, 3H). Analytical HPLC (Method A) RT = 9.37 min, purity = 90%; Factor XIa Ki = 1.8 nM, plasma kallikrein Ki = 120 nM.

Example 149

(9R,13S)-13-(4-{5-chloro-2-[4-({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy}methyl) -1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15 -Preparation of tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

149A. Preparation of 4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine

{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole- prepared as described in Intermediate 16A in DCM (6 ml) 4-day}DAST (0.040 mL, 0.300 mmol) was added to a solution of methanol (95 mg, 0.3 mmol), and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with DCM. The organic layer was concentrated and purified by normal phase chromatography to give 4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6. -Methoxypyrimidine (56 mg, 0.175 mmol, 58.4% yield) was obtained as a clear oil. MS(ESI) m/z: 320.0 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.68 (d, J=1.1 Hz, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.73 (d, J=2.6 Hz, 1H), 7.64 - 7.57 ( m, 1H), 7.53 - 7.48 (m, 1H), 6.46 (d, J=1.1 Hz, 1H), 5.57 (s, 1H), 5.45 (s, 1H), 3.98 - 3.87 (m, 3H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -208.23 (s).

149B. Preparation of 6-{2-[4-(bromomethyl)-1H-1,2,3-triazol-1-yl]-5-chlorophenyl} pyrimidin-4-ol.

4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6 in 33% HBr in AcOH (0.5 ml, 4.14 mmol) A solution of -methoxypyrimidine (56 mg, 0.175 mmol) was heated at 85° C. for 1 hour. The reaction was concentrated to half volume, then 48% aqueous HBr (0.2 ml) was added and heated at 85° C. for 1 hour. The reaction was concentrated and the residue was partitioned between EtOAc and saturated NaHCO ₃ . The layers were separated and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were concentrated and purified by normal phase chromatography to give 6-{2-[4-(bromomethyl)-1H-1,2,3-triazol-1-yl]-5-chlorophenyl}pyri. Midin-4-ol was obtained. MS(ESI) m/z: 368.2(M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 7.87 (d, J=0.9 Hz, 1H), 7.79 (s, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.65 - 7.57 (m, 1H), 7.55 - 7.46 (m, 1H), 6.38 (d, J=1.1 Hz, 1H), 4.60 (s, 2H).

149C. (9R,13S)-13-(4-{5-chloro-2-[4-({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy}methyl) -1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15 -Preparation of tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{5-chloro-2-[4-({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy}methyl) -1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15 -Tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (12.1 mg, 42.1% yield) 6-{2-[4-(bromomethyl)-1H-1,2,3-triazol-1-yl]-5-chlorophenyl} pyrimidine-4 in a manner similar to the procedure described in Example 56. It was prepared using -ol (12.3 mg, 0.033 mmol). MS(ESI) m/z: 704.24 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.23 (s, 1H), 8.82 - 8.71 (m, 2H), 8.66 - 8.60 (m, 2H), 8.57 (d, J=8.2 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.81 (dd, J=8.5, 2.1 Hz, 1H), 7.65 - 7.59 (m, 2H), 7.56 (dd, J=8.4, 4.4 Hz, 1H), 7.51 ( d, J=4.6 Hz, 1H), 7.46 (s, 1H), 6.37 (s, 1H), 5.86 (d, J=11.3 Hz, 1H), 5.77 (s, 2H), 4.03 - 3.91 (m, 3H) ), 3.55 (m., 1H), 2.62 (m, 1H), 2.23 (m, 1H), 2.05 (d, J=10.4 Hz, 1H), 1.86 - 1.73 (m, 1H), 1.41 (m, 1H) ), 1.29 (m, 1H), 0.85 (d, J=6.7 Hz, 3H), 0.39 (m., 1H). Analytical HPLC (Method C): RT = 1.41 min, purity = 95%; Factor XIa Ki = 3.4 nM, plasma kallikrein Ki = 310 nM.

Example 150

(9R,13S)-13-(4-{5-chloro-2-[4-(hydroxylmethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1 ,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), 4,14,16-pentaen-8-one trifluoroacetate production

150A. Preparation of 6-{5-chloro-2-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]phenyl} pyrimidin-4-ol

{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1, prepared as described in Intermediate 16A, in 33% HBr in AcOH (0.6 ml, 4.97 mmol) A solution of 2,3-triazol-4-yl}methanol (65 mg, 0.205 mmol) was heated at 85° C. for 1 hour. The reaction was concentrated to half volume, then 48% aqueous HBr (0.2 ml) was added and heated at 85° C. for 1 hour. The reaction was concentrated and the residue was partitioned between EtOAc and saturated NaHCO ₃ . The layers were separated and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were concentrated and purified by normal phase chromatography to give 6-{5-chloro-2-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyri. Midin-4-ol (13 mg, 20.9% yield) was obtained. MS(ESI) m/z: 304.4(M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.76 (s, 2H), 7.59 (dd, J=8.5, 2.3 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 6.18 (s, 1H), 4.83 - 4.76 (m, 2H).

150B. (9R,13S)-13-(4-{5-chloro-2-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1 ,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), 4,14,16-pentaen-8-one trifluoroacetate production

(9R,13S)-13-(4-{5-chloro-2-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1 ,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6) ),4,14,16-pentaen-8-one trifluoroacetate (1.5 mg, 4.7% yield) was reacted with 6-(5-chloro-2-(4-( It was prepared using hydroxylmethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (13.19 mg, 0.043 mmol). MS(ESI) m/z: 586.20 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.26 (s, 1H), 8.82 (s, 1H), 8.68 (d, J=4.9 Hz, 1H), 8.23 (s, 1H), 7.89 (d, J =1.8 Hz, 1H), 7.78 (d, J=6.4 Hz, 1H), 7.68 - 7.61 (m, 2H), 7.56 (d, J=5.2 Hz, 1H), 7.47 (s, 1H), 6.15 (s , 1H), 5.90 - 5.82 (m, 1H), 4.57 (d, J=4.9 Hz, 2H), 4.00 (s, 3H), 2.68 - 2.60 (m, 1H), 2.32 - 2.22 (m, 1H), 2.07 (m, 1H), 1.88 - 1.78 (m, 1H), 1.50 - 1.43 (m, 1H), 1.40 - 1.29 (m, 1H), 0.88 (d, J=6.7 Hz, 3H), 0.46 - 0.35 ( m, 1H). Analytical HPLC (Method C): RT = 1.19 min, purity = 92%; Factor XIa Ki = 7.3 nM, plasma kallikrein Ki = 1,400 nM.

Example 151

(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] Octadeca-1(18),2( 6),4,14,16-pentaen-8-one trifluoroacetate (10 mg, 20.4% yield) was prepared as described in Intermediate 16 in a manner similar to the procedure described in Example 56. -Chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (21.62 mg, 0.067 mmol) was used to prepare . MS(ESI) m/z: 606.2 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.77 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.53 (t, J=1.3 Hz, 1H), 7.88 (d, J=2.4 Hz) , 1H), 7.77 - 7.72 (m, 1H), 7.69 (s, 1H), 7.68 - 7.64 (m, 1H), 7.52 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 7.14 - 6.84 (m, 1H), 6.35 (s, 1H), 5.97 (dd, J=12.5, 4.2 Hz, 1H), 4.04 (s, 3H), 2.70 (td, J=6.7, 3.1 Hz, 1H) , 2.27 (qd, J=8.5, 4.7 Hz, 1H), 2.12 - 1.92 (m, 2H), 1.65 - 1.53 (m, 1H), 1.45 (ddd, J=14.6, 9.8, 5.3 Hz, 1H), 1.00 (d, J=6.8 Hz, 3H), 0.69 (m, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -77.76 (s), -114.46 (s). Analytical HPLC (Method A): RT = 7.81 min, purity = 98.7%; Factor XIa Ki = 0.27 nM, plasma kallikrein Ki = 54 nM.

Example 152

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-oxo-1,6-dihydro Pyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14 , Preparation of 16-pentaen-8-one trifluoroacetate

152A. Preparation of 4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-methoxypyrimidine

To a solution of 4-(trifluoromethyl)-1H-pyrazole (34.2 mg, 0.251 mmol) in 2 parts DMF (698 μl) was added NaH (12.57 mg, 0.314 mmol) and the reaction was incubated at room temperature for 30 min. It was stirred for a while. 4-(5-Chloro-2-fluorophenyl)-6-methoxypyrimidine (50 mg, 0.210 mmol) prepared as described in Intermediate 5A was added and the solution was stirred at room temperature for 2 hours, Heated at 85°C overnight. The reaction mixture was quenched with water and MeOH and then concentrated. Purified by normal phase chromatography, 4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-methoxypyrimidine (60 mg, 32.3% yield) was obtained. MS(ESI) m/z: 355.3 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.73 (d, J=0.9 Hz, 1H), 7.81 (s, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.70 (s, 1H), 7.59 - 7.53 (m, 1H), 7.51 - 7.47 (m, 1H), 6.36 (d, J=1.1 Hz, 1H), 3.98 - 3.94 (m, 3H).

152B. Preparation of 6-(5-chloro-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyrimidin-4-ol.

6-{5-Chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}pyrimidin-4-ol (23 mg, 25.5% yield) was obtained by the procedure described in Intermediate 9E. Use 4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-methoxypyrimidine (60 mg, 0.169 mmol) in a similar manner. It was manufactured. MS(ESI) m/z: 341.3(M+H) ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.90 (d, J=0.7 Hz, 1H), 7.82 (s, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.63 - 7.55 (m, 1H), 7.53 - 7.47 (m, 1H), 6.27 (d, J=0.9 Hz, 1H).

152C. (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-oxo-1,6-dihydro Pyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14 , Preparation of 16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-oxo-1,6-dihydro Pyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14 , 16-pentaen-8-one trifluoroacetate (20 mg, 40.2% yield) was purified from 6-{5-chloro-2-[4-(trifluoromethyl) in a manner similar to the procedure described in Example 56. -1H-pyrazol-1-yl]phenyl}pyrimidin-4-ol (22.76 mg, 0.067 mmol). MS(ESI) m/z: 623.2 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.85 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.32 (s, 1H), 7.90 - 7.80 (m, 2H), 7.71 - 7.64 ( m, 2H), 7.62 - 7.57 (m, 1H), 7.52 (dd, J=5.2, 1.7 Hz, 1H), 7.49 (s, 1H), 6.20 (d, J=0.7 Hz, 1H), 5.98 (dd , J=12.7, 4.3 Hz, 1H), 4.05 (s, 3H), 2.70 (td, J=6.7, 3.2 Hz, 1H), 2.30 (tt, J=12.7, 4.4 Hz, 1H), 2.13 - 1.94 ( m, 2H), 1.68 - 1.53 (m, 1H), 1.47 (ddd, J=14.9, 9.8, 5.3 Hz, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.70 (m, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -57.99 (s), -77.75 (s). Analytical HPLC (Method A): RT = 8.98 min, purity = 99.1%; Factor XIa Ki = 10 nM, plasma kallikrein Ki = 4,900 nM.

Example 153

(9R,13S)-13-(4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1 ,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), 4,14,16-pentaen-8-one trifluoroacetate production

153A. Preparation of 6-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl} pyrimidin-4-ol

4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl} prepared as described in Example 149A in ACN (1 mL) A solution of -6-methoxypyrimidine (35 mg, 0.109 mmol) was treated with TMSI (75 μL, 0.55 mmol) and heated at 50°C for 6 hours. The reaction was poured into 10% aqueous Na ₂ S ₂ O ₃ . Saturated NaHCO ₃ was added and the mixture was extracted with EtOAc (2x). The combined organic layers were washed with brine, concentrated and purified by normal phase chromatography to give 6-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazole-1- Y]phenyl}pyrimidin-4-ol (14 mg, 41.8% yield) was obtained. MS(ESI) m/z: 306.4(M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.74 (d, J=2.4 Hz, 1H), 7.62 (dd, J=8.5, 2.3 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 6.36 (s, 1H), 5.55 (d, J=48.2 Hz, 1H). ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -208.21 (s).

153B. (9R,13S)-13-(4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1 ,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), 4,14,16-pentaen-8-one trifluoroacetate production

(9R,13S)-13-(4-{5-chloro-2-[4-(fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1 ,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6) ), 4,14,16-pentaen-8-one trifluoroacetate (12 mg, 37% yield) was purified from 6-{5-chloro-2-[4-( trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol to 6-{5-chloro-2-[4-(fluoromethyl)-1H- It was prepared by replacing with 1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (14 mg, 0.046 mmol). MS(ESI) m/z: 588.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.79 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.35 (d, J=3.1 Hz, 1H), 7.88 (d, J=2.4 Hz) , 1H), 7.75 - 7.70 (m, 1H), 7.68 (s, 1H), 7.66 - 7.62 (m, 1H), 7.52 (dd, J=5.3, 1.5 Hz, 1H), 7.48 (s, 1H), 6.29 (s, 1H), 5.96 (dd, J=12.5, 4.2 Hz, 1H), 5.47 (d, J=48.6 Hz, 2H), 4.04 (s, 3H), 2.70 (td, J=6.7, 3.3 Hz) , 1H), 2.33 - 2.20 (m, 1H), 2.12 - 1.92 (m, 2H), 1.66 - 1.53 (m, 1H), 1.52 - 1.37 (m, 1H), 1.00 (d, J=7.0 Hz, 3H) ), 0.69 (m, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -77.74 (s), -207.90 (s). Analytical HPLC (Method A): RT = 7.01 min, purity = 98.5%; Factor XIa Ki = 1.4 nM, plasma kallikrein Ki = 150 nM.

Example 154

1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl} Preparation of phenyl)-1H-1,2,3-triazole-4-carbonitrile trifluoroacetate

1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl} Phenyl)-1H-1,2,3-triazole-4-carbonitrile trifluoroacetate (8 mg, 18% yield) was prepared as described in Intermediate 18 in a manner similar to the procedure described in Example 56. It was prepared using -[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile (17.81 mg, 0.060 mmol) . MS(ESI) m/z: 617.2 (M+H).

¹ H NMR (400MHz, CD ₃ OD) δ 8.93 (s, 1H), 8.79 (s, 1H), 8.75 (d, J=5.1 Hz, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.81 - 7.63 (m, 5H), 7.54 - 7.48 (m, 1H), 6.47 (d, J=0.7 Hz, 1H), 5.99 (dd, J=12.8, 4.4 Hz, 1H), 2.76 - 2.65 (m, 1H) ), 2.34 - 2.22 (m, 1H), 2.09 - 1.94 (m, 2H), 1.65 - 1.40 (m, 2H), 0.99 (d, J=6.8 Hz, 3H), 0.71 - 0.54 (m, 1H). Analytical HPLC (Method A): RT = 9.04 min, purity = 99.0%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 17 nM.

Example 155

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-( ^2H3 )methyl-9-methyl-3,4,7,15 _- tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-( ^2H3 )methyl-9-methyl-3,4,7,15 _- tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (11 mg, 30% yield) was purified as described in Intermediate 33 in a manner similar to the procedure described in Example 56. (9R,13S)-13-amino-3-( ^2H ₃ )methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1 prepared together It was prepared using (18),2(6),4,14,16-pentaen-8-one (15 mg, 0.050 mmol). MS(ESI) m/z: 627.3 (M+H).

¹ H NMR (400MHz, CD ₃ OD) δ 8.81 (s, 1H), 8.77 - 8.66 (m, 2H), 7.89 (d, J=2.2 Hz, 1H), 7.79 - 7.64 (m, 3H), 7.59 - 7.51 (m, 1H), 7.49 (s, 1H), 6.44 (s, 1H), 5.97 (dd, J=12.4, 3.9 Hz, 1H), 2.76 - 2.62 (m, J=6.5, 3.4, 3.4 Hz, 1H), 2.34 - 2.21 (m, 1H), 2.12 - 1.94 (m, 2H), 1.68 - 1.53 (m, 1H), 1.51 - 1.39 (m, 1H), 1.00 (d, J=6.8 Hz, 3H) , 0.78 - 0.63 (m, 1H). Analytical HPLC (Method A): RT = 8.64 min, purity = 99.4%; Factor XIa Ki = 0.14 nM, plasma kallikrein Ki = 33 nM.

Example 156

(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (22 mg, 57% yield) was purified as described in Intermediate 16 in a manner similar to the procedure described in Example 56. 6-{5-chloro-2-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl} pyrimidin-4-ol (16.41 mg, 0.051) prepared together mmol), and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3. It was prepared using 1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (17 mg, 0.051 mmol). MS(ESI) m/z: 642.3 (M+H).

¹ H NMR (400MHz, CD ₃ OD) δ 8.84 (s, 1H), 8.72 (d, J=5.1 Hz, 1H), 8.53 (t, J=1.4 Hz, 1H), 7.89 (d, J=2.2 Hz) , 1H), 7.81 - 7.62 (m, 5H), 7.54 - 7.48 (m, 1H), 6.99 (t, J=54.4 Hz, 1H), 6.35 (d, J=0.7 Hz, 1H), 6.00 (dd, J=12.9, 4.7 Hz, 1H), 2.70 (td, J=6.7, 3.0 Hz, 1H), 2.33 - 2.19 (m, 1H), 2.08 - 1.93 (m, 2H), 1.64 - 1.51 (m, 1H) , 1.51 - 1.39 (m, 1H), 0.99 (d, J=7.0 Hz, 3H), 0.68 - 0.52 (m, 1H). Analytical HPLC (Method A): RT = 10.94 min, purity = 99.0%; Factor XIa Ki = 0.22 nM, plasma kallikrein Ki = 50 nM.

Example 157

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (20 mg, 50% yield) was purified as described in Intermediate 30 in a manner similar to the procedure described in Example 56. (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1 prepared together It was prepared using (18),2(6),4,14,16-pentaen-8-one (17 mg, 0.051 mmol). MS(ESI) m/z: 660.3 (M+H).

¹ H NMR (400MHz, CD ₃ OD) δ 8.81 (d, J=3.7 Hz, 2H), 8.71 (d, J=5.1 Hz, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.81 - 7.62 (m, 5H), 7.56 - 7.46 (m, 1H), 6.44 (s, 1H), 6.00 (dd, J=12.7, 4.5 Hz, 1H), 2.70 (td, J=6.5, 3.0 Hz, 1H), 2.32 - 2.20 (m, 1H), 2.10 - 1.91 (m, 2H), 1.65 - 1.51 (m, 1H), 1.51 - 1.39 (m, 1H), 0.99 (d, J=6.8 Hz, 3H), 0.70 - 0.51 (m, 1H). Analytical HPLC (Method A): RT = 9.74 min, purity = 97.8%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 34 nM.

Example 158

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo [ _12.3.1.0 ^2,6 ]octadeca-1( Preparation of 18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-( ^2H ₃ )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1( 18),2(6),4,14,16-pentaen-8-one trifluoroacetate (12 mg, 36% yield) was prepared as described in Intermediate 36 in a manner similar to the procedure described in Example 56. (9R, _{13S)-13-amino-3-(2H3} ⁾ methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18), It was prepared using 2(6),4,14,16-pentaen-8-one (16 mg, 0.053 mmol). MS(ESI) m/z: 626.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.76 (d, J=0.7 Hz, 1H), 8.10 (s, 1H), 7.86 (d, J=2.2 Hz, 1H), 7.76 - 7.71 (m, 2H) , 7.69 - 7.63 (m, 1H), 7.60 - 7.50 (m, 2H), 7.49 (s, 1H), 7.31 - 7.24 (m, 1H), 6.47 (d, J=0.4 Hz, 1H), 5.81 (dd , J=12.8, 3.3 Hz, 1H), 2.46 (ddd, J=10.3, 6.8, 3.6 Hz, 1H), 2.38 - 2.23 (m, 1H), 2.13 - 1.98 (m, 1H), 1.91 - 1.78 (m , 1H), 1.63 - 1.47 (m, 2H), 1.27 - 1.15 (m, 1H), 1.13 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A): RT = 9.06 min, purity = 99.2%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 8 nM.

Example 159

(9S,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one

159A. Preparation of (R)-N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

4-Chloropicolinaldehyde (5.0 g, 35.3 mmol), CH ₂ Cl ₂ (100 mL), (R)-2-methylpropane-2-sulfinamide (5.14 g, 42.4 mmol) and Cs ₂ CO ₃ in RBF. (34.5 g, 106 mmol) was added. The reaction was stirred at room temperature overnight. The reaction was filtered through Celite®. The filtrate was concentrated and the residue was purified using the ISCO system (0-50% EtOAc/Hep gradient) to give (R)-N-((4-chloropyridin-2-yl)methylene)-2-methyl Propane-2-sulfinamide (6.36 g, 26.0 mmol, 73.6% yield) was obtained as a clear oil.

^1H NMR (400MHz, CDCl ₃ ) δ 8.71 (s, 1H), 8.67 (dd, J=5.3, 0.4 Hz, 1H), 8.05 (dd, J=2.0, 0.4 Hz, 1H), 7.44 (dd, J =5.3, 2.0 Hz, 1H), 1.33 (s, 9H); MS(ESI) m/z: 245.1 (M+H) ⁺ .

159B. Preparation of (R)-N-((R)-1-(4-chloropyridin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide

To RBF, (R)-N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (6.39 g, 26.1 mmol), THF (40 mL), 3-bromoprop -1-N (3.39 mL, 39.2 mmol) and In (4.50 g, 39.2 mmol) were added. The reaction was stirred at 60°C overnight. The reaction was then partitioned between EtOAc (100 ml) and water (50 ml). The organic layer was separated, washed with saturated NaCl (50 ml), dried over MgSO ₄ , filtered and concentrated. The residue was purified using the ISCO system (0-100% EtOAc/Hep gradient) to (R)-N-((R)-1-(4-chloropyridin-2-yl)but-3-en- 1-yl)-2-methylpropane-2-sulfinamide (5.67 g, 19.8 mmol, 76% yield) was obtained as a clear oil.

^1H NMR (500MHz, CDCl ₃ ) δ 8.50 - 8.41 (m, 1H), 7.36 - 7.30 (m, 1H), 7.26 - 7.18 (m, 1H), 5.71 (ddt, J=17.1, 10.3, 6.9 Hz, 1H), 5.12 - 4.99 (m, 2H), 4.77 (d, J=7.4 Hz, 1H), 4.48 (q, J=6.8 Hz, 1H), 2.66 - 2.51 (m, 2H), 1.30 - 1.27 (m , 9H); MS(ESI) m/z: 287.1 (M+H) ⁺ .

159C. Preparation of (R)-tert-butyl (1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate

(R)-N-((R)-1-(4-chloropyridin-2-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (5.67 g, 19.77) to RBF mmol), MeOH (100 mL) and 4 N HCl in dioxane (24.71 mL, 99 mmol) were added. The reaction was stirred at room temperature for 30 minutes. The reaction was then concentrated to give a white solid. To this solid was added CH ₂ Cl ₂ (100 mL), Et ₃ N (5.51 mL, 39.5 mmol) and (Boc) ₂ O (5.51 mL, 23.72 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with CH ₂ Cl ₂ (100 ml), washed with water (100 ml) and saturated NaCl (100 ml), dried over MgSO ₄ , filtered and concentrated. The residue was purified using the ISCO system (0-50% EtOAc/Hex gradient) to give (R)-tert-butyl (1-(4-chloropyridin-2-yl)but-3-en-1-yl. ) Carbamate (4.92 g, 17.40 mmol, 88% yield) was obtained as a clear oil.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.47 (d, J=5.2 Hz, 1H), 7.27 (d, J=1.7 Hz, 1H), 7.21 (dd, J=5.2, 1.9 Hz, 1H), 5.80 - 5.60 (m, 1H), 5.49 (d, J=5.8 Hz, 1H), 5.15 - 5.00 (m, 2H), 4.81 (d, J=6.1 Hz, 1H), 2.67 - 2.50 (m, 2H), 1.50 - 1.39 (m, 9H); MS(ESI) m/z: 283.1 (M+H) ⁺ .

159D. (R)-tert-butyl (1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1- 1) Production of carbamate

(R)-tert-butyl (1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (2.54 g, 15.56 mmol) to RBF, di(adamantane-1) -yl)(butyl)phosphine (0.507 g, 1.415 mmol), K ₂ CO ₃ (5.87 g, 42.4 mmol), pivalic acid (0.433 g, 4.24 mmol) and dioxane (50 mL) were added. The reaction mixture was purged with Ar for 5 minutes. Pd(OAc) ₂ (0.159 g, 0.707 mmol) was added to this mixture, and the reaction was heated at 100°C for 4 hours. The reaction was then partitioned using water (200 mL) and EtOAc (200 mL). The organic layer was separated, washed with water (200 mL) and saturated NaCl (200 mL), dried over MgSO ₄ , filtered, and concentrated to give the crude product, which was then purified using an ISCO system (0-60% EtOAc). /Hex gradient) to purify (R)-tert-butyl (1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl )But-3-en-1-yl)carbamate (4.12 g, 10.06 mmol, 71.1% yield) was obtained as a yellow oil.

^1H NMR (500MHz, CDCl ₃ ) δ 8.82 - 8.78 (m, 1H), 8.36 (s, 1H), 7.34 (s, 1H), 7.32 - 7.30 (m, 1H), 7.23 - 6.96 (m, 1H) , 5.76 - 5.65 (m, 1H), 5.59 (d, J=5.8 Hz, 1H), 5.14 - 5.04 (m, 2H), 4.93 (d, J=5.8 Hz, 1H), 2.67 (t, J=6.1 Hz, 2H), 1.46 (br. s., 9H); MS(ESI) m/z: 410.1 (M+H) ⁺ .

159E. (R)-tert-butyl (1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1- 1) Production of carbamate

Round bottom (R)-tert-butyl (1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-ene -1-yl)carbamate (4.12 g, 10.06 mmol), Zn (2.63 g, 40.3 mmol), MeOH (40 mL) and AcOH (4 mL) were added. The reaction was heated at 40° C. for 10 minutes. The reaction was then cooled to room temperature and partitioned between EtOAc (100 ml) and saturated NaHCO ₃ (100 ml). The organic layer was separated, washed with water (100 ml) and saturated NaCl (100 ml), dried over MgSO ₄ , filtered and concentrated. The residue was purified using the ISCO system (0-30% MeOH/CH ₂ Cl ₂ gradient) to give (R)-tert-butyl (1-(4-(4-amino-1-(difluoromethyl) -1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (3.37 g, 8.88 mmol, 88% yield) was obtained as a yellow oil.

^1H NMR (500MHz, CDCl ₃ ) δ 8.73 - 8.68 (m, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 7.33 (d, J=5.0 Hz, 1H), 7.26 - 7.00 (m , 1H), 5.80 - 5.67 (m, 1H), 5.59 (br. s., 1H), 5.10 (s, 1H), 5.07 (d, J=4.4 Hz, 1H), 4.88 (d, J=6.1 Hz) , 1H), 2.66 (t, J=6.2 Hz, 2H), 1.50 - 1.40 (m, 9H); MS(ESI) m/z: 380.1 (M+H) ⁺ .

159F. tert-Butyl ((1R)-1-(4-(1-(difluoromethyl)-4-(2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2 Preparation of -1)but-3-en-1-yl)carbamate

RBF (R)-tert-butyl (1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en- 1-yl)carbamate (3.37 g, 8.88 mmol), EtOAc (20 mL), 2-methylbut-3-enoic acid (0.889 g, 8.88 mmol) and pyridine (1.44 mL, 17.76 mmol) were added. The solution was cooled in an ice bath and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (7.93 mL, 13.32 mmol) ) was added. The reaction was stirred at 0°C for 2 hours. The reaction was then partitioned between EtOAc (100 ml) and saturated NaHCO ₃ (100 ml). The organic layer was separated, washed with water (100 ml) and brine (100 ml), dried over MgSO ₄ , filtered and concentrated. The residue was purified using the ISCO system (0-80% EtOAc/Hex gradient) to give tert-butyl ((1R)-1-(4-(1-(difluoromethyl)-4-(2-methyl but-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate (3.33 g, 7.22 mmol, 81% yield) was obtained as yellow Obtained as an oil. It was a mixture of two diastereomers.

^1H NMR (500MHz, CDCl ₃ ) δ 8.74 (d, J=5.0 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H), 7.34 - 7.30 (m, 1H), 7.28 - 7.24 (m, 1H) ), 7.22 - 7.06 (m, 2H), 5.98 - 5.83 (m, 1H), 5.76 - 5.65 (m, 1H), 5.51 (br. s., 1H), 5.28 - 5.18 (m, 2H), 5.15 - 5.03 (m, 2H), 4.86 (br. s., 1H), 3.22 - 3.04 (m, 1H), 2.66 (br. s., 2H), 1.50 - 1.42 (m, 9H), 1.33 (dd, J) =7.0, 4.5 Hz, 3H); MS(ESI) m/z: 462.2 (M+H) ⁺ .

159G and 159H. tert-Butyl N-[(9S,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate, and tert-butyl N-[(9R,13R)-3-(difluoro methyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14, Preparation of 16-hexaen-13-yl]carbamate

tert-butyl ((1R)-1-(4-(1-(difluoromethyl)-4-(2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridine in RBF -2-yl)but-3-en-1-yl)carbamate (3.33 g, 7.22 mmol) and EtOAc were added. Second generation Grubbs catalyst (1.531 g, 1.804 mmol) was added to the reaction. The reaction was refluxed under Ar for 2 days. The reaction was concentrated. The residue was purified using the ISCO system (0-100% EtOAc/Hex gradient followed by 100% EtOAc). Two diastereomers were separated. The first compound to emerge from the column is 159G, tert-butyl N-[(9S,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatri Cyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (490 mg, 1.13 mmol, 15.7% yield ) was.

^1H NMR (400MHz, CDCl ₃ ) δ 8.72 (d, J=5.1 Hz, 1H), 7.80 (s, 1H), 7.42 (s, 1H), 7.27 (m, 1H), 7.20 (br. s., 1H), 6.87 (s, 1H), 6.41 (d, J=7.5 Hz, 1H), 5.77 (ddd, J=15.2, 11.0, 4.0 Hz, 1H), 4.89 - 4.70 (m, 2H), 3.19 - 3.08 (m, 1H), 3.03 (d, J=12.5 Hz, 1H), 2.03 - 1.92 (m, 1H), 1.50 (s, 9H), 1.20 (d, J=6.6 Hz, 3H); MS(ESI) m/z: 434.1 (M+H) ⁺ . The second compound to emerge from the column is 159H, tert-butyl N-[(9R,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatri Cyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (460 mg, 1.06 mmol, 14.7% yield ) was.

^1H NMR (400MHz, CDCl ₃ ) δ 8.71 (d, J=5.1 Hz, 1H), 7.83 (s, 1H), 7.37 (d, J=5.1 Hz, 1H), 7.26 (d, J=2.6 Hz, 1H), 6.89 (s, 1H), 6.68 (br. s., 1H), 6.28 (br. s., 1H), 5.84 - 5.69 (m, 1H), 5.47 - 5.32 (m, 1H), 4.82 ( br. s., 1H), 3.11 - 2.90 (m, 2H), 2.15 - 1.98 (m, 1H), 1.52 - 1.44 (m, 9H), 1.37 (d, J=6.6 Hz, 3H); MS(ESI) m/z: 434.1 (M+H) ⁺ .

159I. tert-Butyl N-[(9S,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

tert-butyl N-[(9S,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (485 mg, 1.119 mmol), EtOH (35 mL) and PtO ₂ (127 mg, 0.559 mmol) was added. The reaction was stirred under a H ₂ balloon for 1 hour. The reaction was carefully filtered through Celite® and the filtrate was concentrated. The residue was purified using the ISCO system (0-10% MeOH/CH ₂ Cl ₂ gradient) to give tert-butyl N-[(9S,13R)-3-(difluoromethyl)-9-methyl-8. -oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]car Bamate (370 mg, 0.850 mmol, 76% yield) was obtained as a beige solid.

^1H NMR (400MHz, CDCl ₃ ) δ 8.75 (d, J=5.1 Hz, 1H), 7.63 (s, 1H), 7.46 (s, 1H), 7.35 (s, 1H), 7.31 (m, J=3.5 Hz, 1H), 6.81 (br. s., 1H), 5.81 (d, J=7.9 Hz, 1H), 4.88 (br. s., 1H), 2.62 (td, J=6.5, 2.6 Hz, 1H) , 2.13 - 1.99 (m, 1H), 1.90 - 1.77 (m, 1H), 1.69 - 1.62 (m, 1H), 1.56 - 1.51 (m, 1H), 1.49 - 1.41 (m, 9H), 1.31 - 1.17 ( m, 1H), 1.03 (d, J=6.8 Hz, 3H), 0.41 (d, J=12.1 Hz, 1H); MS(ESI) m/z: 436.1 (M+H) ⁺ .

159J. (9S,13R)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of ,2(6),4,14,16-pentaen-8-one

To RBF, tert-butyl N-[(9S,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (370 mg, 0.850 mmol), dioxane (1 mL), MeOH (1 mL) and 4 N HCl (6.37 mL, 25.5 mmol) were added. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated to give the product as the HCl salt. This HCl salt was dissolved in MeOH and added to a pre-rinsed Agilent® Stratosphere SPE PL-HCO ₃ MP resin cartridge. Gravity filtration eluting with MeOH gave a clear, slightly brown filtrate. Concentrate to obtain (9S,13R)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-8-one (285 mg, 0.850 mmol, 100% yield) was obtained as a light brown solid. MS(ESI) m/z: 336.1 (M+H) ⁺ .

159K. (9S,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one

(9S,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6),4,14,16-pentaen-8-one (230 mg, 360 μmol, 42.3% yield) was prepared as described in Intermediate 9 in a manner similar to the procedure described in Example 56. Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (331 mg, 0.850 mmol), and (9S,13R)-13-amino -3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14 It was prepared using 16-pentaen-8-one (285 mg, 0.850 mmol).

¹ H NMR (400MHz, CD ₃ OD) δ 8.90 (s, 1H), 8.76 (d, J=5.1 Hz, 1H), 8.35 (s, 1H), 7.90 (d, J=2.4 Hz, 1H), 7.78 - 7.73 (m, 2H), 7.71 (d, J=0.7 Hz, 1H), 7.68 (t, 1H), 7.65 (s, 1H), 7.55 - 7.53 (m, 1H), 6.39 (d, J=0.9 Hz, 1H), 6.03 (dd, J=12.8, 4.4 Hz, 1H), 2.73 (td, J=6.5, 3.0 Hz, 1H), 2.31 (tt, J=12.8, 4.3 Hz, 1H), 2.11 - 1.97 (m, 2H), 1.67 - 1.44 (m, 2H), 1.01 (d, J=7.0 Hz, 3H), 0.64 (br. s., 1H); MS(ESI) m/z: 626.1 (M+H) ⁺ . Analytical HPLC (Method A): RT = 7.96 min, purity = 95.0%; Factor XIa Ki = 14 nM, plasma kallikrein Ki = 880 nM.

Example 160

(9R,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one

160A. tert-Butyl N-[(9R,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,14,16-pentaen-13-yl] carbamate

tert-butyl N-[(9R,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (450 mg, 1.038 mmol), EtOH (35 mL) and PtO ₂ (118 mg, 0.519 mmol) was added. The reaction was stirred under H ₂ balloon for 1 hour. The reaction was carefully filtered through Celite® and the filtrate was concentrated. The residue was purified using the ISCO system (0-10% MeOH/CH ₂ Cl ₂ gradient) to give tert-butyl N-[(9R,13R)-3-(difluoromethyl)-9-methyl-8. -oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]car Bamate (300 mg, 0.689 mmol, 66.4% yield) was obtained as a beige solid.

^1H NMR (400MHz, CDCl ₃ ) δ 8.73 (d, J=5.3 Hz, 1H), 7.69 (s, 1H), 7.40 (d, J=5.1 Hz, 1H), 7.30 (m, J=4.2 Hz, 1H), 6.49 (br. s., 1H), 5.90 (d, J=7.0 Hz, 1H), 4.88 (br. s., 1H), 2.25 - 2.14 (m, 1H), 2.07 (d, J= 9.5 Hz, 1H), 1.91 - 1.77 (m, 1H), 1.47 (s, 11H), 1.27 (d, J=6.8 Hz, 3H), 0.74 (d, J=11.2 Hz, 1H); MS(ESI) m/z: 436.1 (M+H) ⁺ .

160B. (9R,13R)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of ,2(6),4,14,16-pentaen-8-one

To RBF, tert-butyl N-[(9R,13R)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (300 mg, 0.689 mmol), dioxane (1 mL), MeOH (1 mL) and 4 N HCl (6.37 mL, 25.5 mmol) were added. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated to give the product as the HCl salt. This HCl salt was dissolved in MeOH and added to a pre-rinsed Agilent® Stratosphere SPE PL-HCO ₃ MP resin cartridge. Gravity filtration eluting with MeOH gave a clear, slightly brown filtrate. Concentrate to obtain (9R,13R)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-8-one (220 mg, 0.656 mmol, 95% yield) was obtained as a light brown solid. MS(ESI) m/z: 336.1 (M+H) ⁺ .

160C. (9R,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one.

(9R,13R)-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6),4,14,16-pentaen-8-one (140 mg, 219 μmol, 33.4% yield) was prepared as described in Intermediate 9 in a manner similar to the procedure described in Example 56. Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (255 mg, 0.656 mmol), and (9R,13R)-13-amino -3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14 It was prepared using 16-pentaen-8-one (225 mg, 0.656 mmol).

¹ H NMR (400MHz, CD ₃ OD) δ 8.83 (s, 1H), 8.74 (d, J=5.1 Hz, 1H), 8.36 (s, 1H), 7.91 (d, J=2.2 Hz, 1H), 7.79 (s, 1H), 7.78 - 7.74 (m, 1H), 7.69 (t, 1H), 7.68 - 7.66 (m, 1H), 7.60 (s, 1H), 7.51 (d, J=4.8 Hz, 1H), 6.42 (d, J=0.7 Hz, 1H), 6.07 (dd, J=12.7, 4.3 Hz, 1H), 2.38 - 2.28 (m, 1H), 2.25 - 2.15 (m, 1H), 2.05 - 1.90 (m, 2H), 1.64 - 1.50 (m, 2H), 1.27 (d, J=6.8 Hz, 3H), 0.83 (d, J=13.6 Hz, 1H); MS(ESI) m/z: 626.1 (M+H) ⁺ . Analytical HPLC (Method A): RT = 10.37 min, purity = 97.0%; Factor XIa Ki = 18 nM, plasma kallikrein Ki = 3,200 nM.

Example 161

(9R,13S)-13-{4-[5-chloro-2-(pyridin-3-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9- Preparation of dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl] prepared in Example 138 in a microwave vial. -3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8 -one (0.02 g, 0.035 mmol), pyridin-3-ylboronic acid (4.76 mg, 0.039 mmol), 3 M aqueous K ₃ PO ₄ (0.035 ml, 0.106 mmol) and THF (1 ml) were added. Ar was bubbled through the reaction for a few minutes, then (DtBPF)PdCl ₂ (1.15 mg, 1.761 μmol) was added. The reaction mixture was microwaved at 150° C. for 1 hour, cooled to room temperature, and concentrated. Purified by reverse phase chromatography, (9R,13S)-13-{4-[5-chloro-2-(pyridin-3-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene -8-one trifluoroacetate (3.21 mg, 12% yield) was obtained as a yellow solid. MS(ESI) m/z: 566.2 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.79 - 8.68 (m, 4H), 8.34 (dt, J=8.2, 1.7 Hz, 1H), 7.90 (dd, J=8.0, 5.8 Hz, 1H), 7.81 ( d, J=2.2 Hz, 1H), 7.71 - 7.66 (m, 2H), 7.57 (d, J=8.3 Hz, 1H), 7.53 - 7.47 (m, 2H), 6.52 (d, J=0.5 Hz, 1H) ), 5.98 - 5.90 (m, 1H), 4.04 (s, 3H), 2.74 - 2.64 (m, 1H), 2.30 - 2.19 (m, 1H), 2.10 - 1.93 (m, 2H), 1.63 - 1.53 (m , 1H), 1.50 - 1.40 (m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.77 - 0.61 (m, 1H). Analytical HPLC (Method A): RT = 4.22 min, 99.8% purity; Factor XIa Ki = 100 nM, plasma kallikrein Ki = 5,700 nM.

Example 162

(9R,13S)-13-(4-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]phenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ] Preparation of octadeca-1(18),2(6),4,14,16-pentaen-8-one

162A. Preparation of 6-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol

6-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]phenyl} pyrimidin-4-ol is reacted with Cu ₂ 6-(2-azido-5-chlorophenyl)pyrimidin-4-ol (0.9 g, 3.44 mmol) and 2-methylbut-3-yn-2-ol (0.289 g) in the presence of O (0.05 g) , 3.44 mmol) was prepared by condensation of a solution of ACN (5 ml). The product was obtained as an oil (0.5 g) after ISCO silica gel chromatography using hexane:EtOAc as eluent.

^1H NMR (400MHz, CDCl ₃ ) δ 8.60 - 8.57 (m, 1H), 7.65 - 7.59 (m, 1H), 7.56 - 7.53 (m, 1H), 7.37 - 7.32 (m, 1H), 6.76 - 6.72 ( m, 1H), 3.95 (s, 3H), 3.43 - 3.30 (m, 1H), 1.52 (s, 6H). The oil was then dissolved in AcOH (1 ml), then 48% aqueous HBr (0.5 ml) was added thereto and the reaction was sealed. The reaction mixture was heated at 80° C. for 2 hours and then concentrated to add sticky solid and water (10 ml). A solid precipitated and the solution was collected by decanting. The solid was washed several times with water, the residue was dissolved in MeOH and the solution was concentrated to give 6-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3 -Triazol-1-yl]phenyl}pyrimidin-4-ol (0.15 g, 13%) was obtained as a foam. LCMS m/z = 332.1(M+H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.51 - 11.06 (m, 1H), 8.33 - 8.09 (m, 1H), 7.90 - 7.78 (m, 1H), 7.71 (t, J=7.9 Hz, 1H), 7.39 - 7.29 (m, 1H), 6.87 - 6.68 (m, 1H), 5.80 - 5.66 (m, 1H), 5.27 - 5.17 (m, 1H), 2.12 (s, 6H).

162B. (9R,13S)-13-(4-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]phenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ] Preparation of octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]phenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one was reacted with (6-{5-) using the HATU, DBU coupling methodology as described in Example 56. Chloro-2-[4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (0.01 g, 0.030 mmol) and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18) ,2(6),4,14,16-pentaen-8-one (0.010 g, 0.030 mmol) was coupled as a solid (4.2 mg, 21% yield). MS m/z = 651.1 ( M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.46 - 9.40 (m, 1H), 8.88 - 8.82 (m, 1H), 8.72 - 8.65 (m, 1H), 8.40 - 8.36 (m, 1H), 8.01 - 7.93 (m, 2H), 7.89 (s, 1H), 7.72 - 7.68 (m, 1H), 7.68 - 7.61 (m, 1H), 7.46 - 7.40 (m, 1H), 6.63 - 6.57 (m, 1H), 5.94 - 5.85 (m, 1H), 5.70 - 5.64 (m, 1H), 5.15 - 5.08 (m, 1H), 2.71 - 2.61 (m, 1H), 2.56(s, 3H), 2.35 - 2.16 (m, 1H) ), 2.08 - 2.04 (m, 4H), 2.07 - 1.79 (m, 1H), 1.56 - 1.26 (m, 1H), 0.93 - 0.79 (d, 3H), 0.44 - 0.24 (m, 1H). Analytical HPLC (Method B): RT = 1.75 min, purity = 97%; Factor XIa Ki = 1 nM, plasma kallikrein Ki = 230 nM.

Example 163

(9R,13S)-3-(difluoromethyl)-9-methyl-13-(6-oxo-4-{2-[4-(trifluoromethyl)-1H-1,2,3-tria zol-1-yl]phenyl}-1,6-dihydropyrimidin-1-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of ,2(6),4,14,16-pentaen-8-one

(9R,13S)-3-(difluoromethyl)-9-methyl-13-(6-oxo-4-{2-[4-(trifluoromethyl)-1H-1,2,3-tria zol-1-yl]phenyl}-1,6-dihydropyrimidin-1-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) ,2(6),4,14,16-pentaen-8-one was reacted with (6-{2-[4-(trifluoromethyl)) using the HATU, DBU coupling methodology as described in Example 56. -1H-1,2,3-triazol-1-yl]phenyl} pyrimidin-4-ol (0.012 g, 0.04 mmol) and (9R,13S)-13-amino-3-(difluoromethyl) -9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,14,16-pentaen-8-one (0.013 g, 0.04 mmol) was prepared as a solid through coupling (1.6 mg, 6.2% yield) by LCMS m/z = 626.2 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.46 - 9.42 (m, 1H), 9.20 - 9.15 (m, 1H), 8.76 - 8.67 (m, 2H), 7.89 - 7.83 (m, 2H), 7.80 - 7.73 (m, 3H), 7.70 - 7.64 (m, 1H), 7.46 - 7.39 (m, 1H), 6.42 - 6.36 (m, 1H), 5.94 - 5.86 (m, 1H), 2.70 - 2.60 (m, 1H) ), 2.31 - 2.18 (m, 1H), 2.10 - 1.94 (m, 1H), 1.88 - 1.77 (m, 1H), 1.52 - 1.28 (m, 2H), 0.91 - 0.82 (d, 3H), 0.49 - 0.19 (m, 1H). Analytical HPLC (Method B) RT = 1.65 min, purity = 96%; Factor XIa Ki = 10 nM, plasma kallikrein Ki = 5,900 nM.

Example 164

(9R,13S)-3-(difluoromethyl)-13-(4-{5-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1 -yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca -Preparation of 1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-3-(difluoromethyl)-13-(4-{5-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1 -yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one was reacted with (6-{5-fluoro-2-[ 4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (0.015 g, 0.05 mmol) and (9R,13S)-13-amino- 3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,14, Prepared as a solid (8 mg, 26% yield) via coupling with 16-pentaen-8-one (0.015 g, 0.05 mmol), LCMS m/z = 644.2 (M+H).

^1H NMR (400MHz, CD ₃ OD) δ 8.80 - 8.72 (m, 3H), 7.82 - 7.78 (m, 1H), 7.75-7.70 (m, 2H), 7.66 - 7.60 (m, 2H), 7.52 - 7.43 (m, 1H), 6.44 - 6.41 (m, 1H), 6.01-5.95 (m, 1H), 2.75 - 2.66 (m, 1H), 2.38 - 2.25 (m, 1H), 2.08 - 1.92 (m, 2H) , 1.64 - 1.39 (m, 2H), 1.07 - 0.95 (d, 3H), 0.79 - 0.54 (m, 1H). Analytical HPLC (Method A) RT = 8.22 min, purity = 99%; Factor XIa Ki = 5 nM, plasma kallikrein Ki = 1,100 nM.

Example 165

(9R,13S)-13-{4-[5-chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4 Preparation of 14,16-pentaen-8-one trifluoroacetate

165A. Preparation of 6-(5-chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

6-(5-chloro-2-(4-ethoxy-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol, hydrobromide (0.027 g) in DCM (1 ml) , 0.068 mmol), AlCl ₃ (0.090 g, 0.68 mmol) was added. The reaction was microwaved at 100°C for 10 minutes and cooled to room temperature. The reaction was then cooled in a dry ice/acetone bath and MeOH (1 ml) was added slowly. The reaction was allowed to warm to room temperature and the reaction was stirred until a solution was formed. 1 N HCl (1 ml) was added and the resulting mixture was concentrated to dryness. Purified by reverse phase chromatography, 6-(5-chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (0.012 g, 61.2 % yield) was obtained as a white solid. MS(ESI) m/z: 290.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.11 (s, 1H), 7.82 (d, J=2.4 Hz, 1H), 7.72 - 7.67 (m, 1H), 7.62 - 7.57 (m, 1H), 7.44 ( s, 1H), 6.27 (d, J=0.7 Hz, 1H).

165B. (9R,13S)-13-{4-[5-chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 Preparation of 14,16-pentaen-8-one trifluoroacetate.

(9R,13S)-13-{4-[5-chloro-2-(4-hydroxy-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 ,14,16-pentaen-8-one trifluoroacetate (1.42 mg, 4.9% yield) was purified from 6-(5-chloro-2-(4-hydroxy-1H) in a manner similar to the procedure described in Example 162. -1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (0.012 g, 0.041 mmol) and (9R,13S)-13-amino-3 prepared as described in Intermediate 32, 9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one ( It was prepared using 0.012 g, 0.041 mmol). MS(ESI) m/z: 572.3 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.88 (s, 1H), 8.72 (d, J=5.2 Hz, 1H), 7.87 (d, J=2.2 Hz, 1H), 7.71 - 7.68 (m, 2H) , 7.59 (d, J=8.5 Hz, 1H), 7.52 (dd, J=5.2, 1.7 Hz, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 6.22 (d, J=0.8 Hz, 1H), 5.98 (dd, J=12.7, 4.1 Hz, 1H), 4.05 (s, 3H), 2.75 - 2.66 (m, 1H), 2.36 - 2.25 (m, 1H), 2.11 - 1.96 (m, 2H) , 1.65 - 1.55 (m, 1H), 1.52 - 1.41 (m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.75 - 0.61 (m, 1H). Analytical HPLC (Method A): RT = 6.12 min, 97.7% purity; Factor XIa Ki = 13 nM, plasma kallikrein Ki = 750 nM.

Example 166

5-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)pyridine-3-carboni Manufacture of trills.

5-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)pyridine-3-carboni Tril, 2 trifluoroacetate (1.5 mg, 5% yield) was reacted with pyridin-3-ylboronic acid (4.76 mg, 0.039 mmol) in a manner similar to the procedure described in Example 161 (5-cyanopyridin-3-yl). ) It was prepared by replacing it with boronic acid (5.73 mg, 0.039 mmol). MS(ESI) m/z: 591.2 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.84 (d, J=1.9 Hz, 1H), 8.79 (s, 1H), 8.72 (d, J=5.2 Hz, 1H), 8.64 (d, J=2.2 Hz) , 1H), 8.08 (t, J=2.1 Hz, 1H), 7.75 (d, J=2.2 Hz, 1H), 7.67 - 7.62 (m, 2H), 7.54 - 7.47 (m, 3H), 6.43 (d, J=0.8 Hz, 1H), 6.00 - 5.94 (m, 1H), 4.04 (s, 3H), 2.74 - 2.66 (m, 1H), 2.31 - 2.23 (m, 1H), 2.11 - 1.94 (m, 2H) , 1.64 - 1.54 (m, 1H), 1.51 - 1.42 (m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.75 - 0.60 (m, 1H). Analytical HPLC (Method A): RT = 6.86 min, 99.5% purity; Factor XIa Ki = 58 nM, plasma kallikrein Ki = 6,500 nM.

Example 167

(9R,13S)-13-{4-[5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4 Preparation of 14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 ,14,16-pentaen-8-one trifluoroacetate (3.96 mg, 9.6% yield) was prepared as described in Intermediate 13 in a manner similar to the procedure described in Example 162. -(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol hydrobromide (0.022 g, 0.057 mmol), and (prepared as described in Intermediate 32 9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, Prepared using 14,16-pentaen-8-one (0.017 g, 0.057 mmol). MS(ESI) m/z: 596.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.85 (s, 1H), 8.72 (d, J=5.1 Hz, 1H), 7.88 - 7.86 (m, 2H), 7.72 - 7.67 (m, 2H), 7.59 ( d, J=8.6 Hz, 1H), 7.51 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.17 (d, J=0.9 Hz, 1H), 5.98 (dd, J=12.7 , 4.3 Hz, 1H), 4.04 (s, 3H), 2.75 - 2.66 (m, 1H), 2.34 - 2.24 (m, 1H), 2.12 - 1.93 (m, 3H), 1.66 - 1.40 (m, 2H), 1.03 - 0.94 (m, 5H), 0.81 - 0.58 (m, 3H). Analytical HPLC (Method A): RT = 7.43 min, 98.0% purity; Factor XIa Ki = 3.2 nM, plasma kallikrein Ki = 210 nM.

Example 168

Methyl 4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl} Preparation of benzoate

168A. Preparation of methyl 4-chloro-2-(6-methoxypyrimidin-4-yl)benzoate, and

168B. Preparation of 4-chloro-2-(6-methoxypyrimidin-4-yl)benzoic acid

Suspension of 4-chloro-6-methoxypyrimidine (0.067 g, 0.466 mmol) and (5-chloro-2-(methoxycarbonyl)phenyl)boronic acid (0.1 g, 0.466 mmol) in ACN (1.8 ml) was purged with Ar for a few minutes, then 2 M Na ₂ CO ₃ aqueous (0.47 ml, 0.94 mmol) was added, followed by Pd(Ph ₃ P) ₄ (0.027 g, 0.023 mmol). The vial was capped, microwaved at 130°C for 0.5 hours, and then cooled to room temperature. The reaction was diluted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by normal phase chromatography gave methyl 4-chloro-2-(6-methoxypyrimidin-4-yl)benzoate (0.086 g, 66% yield) as a colorless oil. MS(ESI) m/z: 279.0 (M+H) ⁺ . The aqueous layer from the work-up was neutralized using 1 N HCl to give a white cloudy suspension. The mixture was filtered, the solid was rinsed with water, and air-dried to give 4-chloro-2-(6-methoxypyrimidin-4-yl)benzoic acid (0.026 g, 21% yield) as a white solid. MS(ESI) m/z: 265.0 (M+H) ⁺ .

168C. Preparation of methyl 4-chloro-2-(6-hydroxypyrimidin-4-yl)benzoate

Methyl 4-chloro-2-(6-hydroxypyrimidin-4-yl)benzoate (0.046 g, 56% yield) was prepared as 4-(5-chloro-2-( 1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-6-methoxypyrimidine was reacted with methyl 4-chloro-2-(6-methoxypyrimidin-4-yl)benzoate ( 0.086 g, 0.309 mmol). MS(ESI) m/z: 265.1 (M+H) ⁺ .

¹ H NMR (500 MHz, CD ₃ OD) δ 8.19 (d, J=1.1 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.62 - 7.57 (m, 2H), 6.57 (d, J= 0.8 Hz, 1H), 3.76 (s, 3H).

168D. Methyl 4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl} Preparation of benzoate trifluoroacetate

Methyl 4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}benzoate trifluoroacetate (0.067 g , 58% yield) was prepared as described in Example 168C in a manner similar to the procedure described in Example 56, and methyl 4-chloro-2-(6-hydroxypyrimidin-4-yl)benzoate (0.046 g, It was prepared using 0.174 mmol). MS(ESI) m/z: 547.2 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.99 (s, 1H), 8.74 (d, J=5.2 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.75 (s, 1H), 7.62 (d, J=1.9 Hz, 1H), 7.59 (dd, J=8.3, 2.2 Hz, 1H), 7.55 (dd, J=5.2, 1.7 Hz, 1H), 7.50 (s, 1H), 6.62 (s, 1H), 6.07 (dd, J=12.7, 4.1 Hz, 1H), 4.05 (s, 3H), 3.75 (s, 3H), 2.76 - 2.68 (m, 1H), 2.41 - 2.33 (m, 1H), 2.14 - 2.03 (m, 2H), 1.67 - 1.58 (m, 1H), 1.55 - 1.45 (m, 1H), 1.02 (d, J=6.9 Hz, 3H), 0.79 - 0.66 (m, 1H). Analytical HPLC (Method A): RT = 6.69 min, 99.9% purity; Factor XIa Ki = 27 nM, plasma kallikrein Ki = 650 nM.

Example 169

(9R,13S)-13-{4-[3-chloro-6-(4-ethoxy-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo -1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2 (6), Preparation of 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[3-chloro-6-(4-ethoxy-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo -1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2 (6),4,14,16-pentaen-8-one trifluoroacetate (22 mg, 41.7% yield) was purified from 6-(3-chloro-6-(4) in a manner similar to the procedure described in Example 162. -Ethoxy-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol, hydrobromide (0.030 g, 0.072 mmol) and prepared as described in Intermediate 32 (9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6), Prepared using 4,14,16-pentaen-8-one (0.025 g, 0.072 mmol). MS(ESI) m/z: 618.4 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.87 (s, 1H), 8.73 (d, J=5.1 Hz, 1H), 7.82 (t, J=8.1 Hz, 1H), 7.71 (s, 1H), 7.66 (s, 1H), 7.56 - 7.47 (m, 3H), 6.54 (s, 1H), 6.00 (dd, J=12.5, 4.0 Hz, 1H), 4.13 (q, J=7.0 Hz, 2H), 4.05 ( s, 3H), 2.76 - 2.65 (m, 1H), 2.36 - 2.24 (m, 1H), 2.14 - 1.95 (m, 2H), 1.67 - 1.54 (m, 1H), 1.53 - 1.41 (m, 1H), 1.35 (t, J=7.0 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H), 0.77 - 0.59 (m, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -77.75 (s), -115.15 (s). Analytical HPLC (Method A): RT = 7.32 min, 99.7% purity; Factor XIa Ki = 0.88 nM, plasma kallikrein Ki = 95 nM.

Example 170

(9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo -1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2 (6), Preparation of 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo -1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2 (6),4,14,16-pentaen-8-one trifluoroacetate (0.02 g, 42.8% yield) was prepared as described in Intermediate 14 in a manner similar to the procedure described in Example 160. 3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol (0.021 g, 0.063 mmol), and intermediate (9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18) prepared as described in 32 ,2(6),4,14,16-pentaen-8-one (0.022 g, 0.063 mmol) was used. MS(ESI) m/z: 614.4 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.85 (s, 1H), 8.74 (d, J=5.1 Hz, 1H), 7.88 - 7.78 (m, 2H), 7.71 (s, 1H), 7.57 - 7.47 ( m, 3H), 6.51 (s, 1H), 6.00 (dd, J=12.7, 4.1 Hz, 1H), 4.05 (s, 3H), 2.76 - 2.65 (m, 1H), 2.37 - 2.24 (m, 1H) , 2.14 - 1.89 (m, 3H), 1.67 - 1.39 (m, 2H), 1.05 - 0.90 (m, 5H), 0.77 - 0.60 (m, 3H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -77.75 (s), -115.19 (s). Analytical HPLC (Method A): RT = 7.35 min, 99.2% purity; Factor XIa Ki = 0.93 nM, plasma kallikrein Ki = 95 nM.

Example 171

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4,14,16-pentaene-8- Preparation of ontrifluoroacetate

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4,14,16-pentaene-8- 6-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)pyrimidine-4 was purified from trifluoroacetate (0.016 g, 40.1% yield) in a manner similar to the procedure described in Example 162. -ol hydrobromide (0.021 g, 0.057 mmol) and (9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3] prepared as described in Intermediate 32. .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.02 g, 0.057 mmol) was used. MS(ESI) m/z: 575.3 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 9.05 (s, 1H), 8.77 (d, J=5.1 Hz, 1H), 7.85 - 7.79 (m, 1H), 7.75 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.55 (dd, J=5.3, 1.5 Hz, 1H), 7.50 (s, 1H), 6.60 (s, 1H), 6.08 (dd, J=12.7, 4.3 Hz, 1H), 4.06 (s, 3H), 2.77 - 2.67 (m, 1H), 2.45 - 2.34 (m, 1H), 2.16 - 2.04 (m, 2H), 1.70 - 1.44 (m, 2H), 1.02 (d, J=7.0 Hz, 3H), 0.81 - 0.64 (m, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -59.04 (s), -77.76 (s), -115.37 (s). Analytical HPLC (Method A): RT = 8.30 min, 99.3% purity; Factor XIa Ki = 12 nM, plasma kallikrein Ki = 190 nM.

Example 172

(9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo -1,6-dihydropyrimidin-1 _- yl}-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 Preparation of (18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo -1,6-dihydropyrimidin-1 _- yl}-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18),2(6),4,14,16-pentaen-8-one (5.4 mg, 22.0% yield) was prepared as described in intermediate 14 in a manner similar to the procedure described in 160, 6-(3 -Chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol (0.013 g, 0.040 mmol), and Intermediate 36 (9R, _13S )-13-amino-3-( ^2H3 )methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca- prepared as described in It was prepared using 1(18),2(6),4,14,16-pentaen-8-one (0.012 g, 0.040 mmol). MS(ESI) m/z: 616.3 (M+H) ⁺ .

^1H NMR (400MHz, CD ₃ OD) δ 8.17 (s, 1H), 7.84 - 7.73 (m, 3H), 7.62 - 7.54 (m, 2H), 7.50 - 7.46 (m, 2H), 7.32 (d, J =7.5 Hz, 1H), 6.55 (s, 1H), 5.82 (dd, J=12.8, 3.1 Hz, 1H), 2.52 - 2.42 (m, 1H), 2.38 - 2.27 (m, 1H), 2.15 - 2.03 ( m, 1H), 1.97 - 1.81 (m, 2H), 1.62 - 1.49 (m, 2H), 1.26 - 1.10 (m, 4H), 1.00 - 0.90 (m, 2H), 0.73 - 0.63 (m, 2H). Analytical HPLC (Method A): RT = 8.18 min, 100% purity; Factor XIa Ki = 0.36 nM, plasma kallikrein Ki = 45 nM.

Example 173

(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( Preparation of 18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-8-one trifluoroacetate (0.0215 g, 56.3% yield) was prepared as described in Intermediate 11 in a manner similar to the procedure described in Example 160. 6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (0.018 g, 0.050 mmol), and (9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 prepared as described in Intermediate 32. ]Octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.015 g, 0.050 mmol) was used. MS(ESI) m/z: 642.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.82 (s, 1H), 8.78 (s, 1H), 8.70 (d, J=5.1 Hz, 1H), 7.91 - 7.83 (m, 1H), 7.70 (s, 1H), 7.59 (dd, J=8.6, 1.3 Hz, 1H), 7.53 (dd, J=5.2, 1.4 Hz, 1H), 7.48 (s, 1H), 6.65 (s, 1H), 6.00 (dd, J =12.7, 4.1 Hz, 1H), 4.05 (s, 3H), 2.74 - 2.64 (m, 1H), 2.33 - 2.22 (m, 1H), 2.12 - 1.93 (m, 2H), 1.66 - 1.39 (m, 2H) ), 1.00 (d, J=7.0 Hz, 3H), 0.75 - 0.58 (m, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -62.57 (s), -77.74 (s), -114.95 (s). Analytical HPLC (Method A): RT = 8.64 min, 99.6% purity; Factor XIa Ki = 0.11 nM, plasma kallikrein Ki = 13 nM.

Example 174

1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl) -Preparation of 1H-1,2,3-triazole-4-carbonitrile trifluoroacetate

1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl) -1H-1,2,3-triazole-4-carbonitrile trifluoroacetate (0.0105 g, 0.015 mmol, 23.13% yield) was prepared as described in Intermediate 12, in a manner similar to the procedure described in Example 160. 1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (0.02 g, 0.063 mmol), and (9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca prepared as described in Intermediate 32. -Prepared using 1(18),2(6),4,14,16-pentaen-8-one (0.019 g, 0.063 mmol). MS(ESI) m/z: 599.2 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.93 (s, 1H), 8.78 - 8.74 (m, 2H), 7.93 - 7.86 (m, 1H), 7.70 (s, 1H), 7.60 (dd, J=8.7 , 1.4 Hz, 1H), 7.53 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.65 (s, 1H), 5.99 (dd, J=12.4, 3.6 Hz, 1H), 4.05 (s, 3H), 2.75 - 2.65 (m, 1H), 2.35 - 2.23 (m, 1H), 2.13 - 1.95 (m, 2H), 1.67 - 1.41 (m, 2H), 1.01 (d, J=6.8 Hz) , 3H), 0.78 - 0.60 (m, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -77.72 (s), -114.94 (s). Analytical HPLC (Method A): RT = 7.85 min, 99.2% purity; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 6 nM.

Example 175

(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3-( ^2H ₃ )methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ] Preparation of octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3-( ^2H ₃ )methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (0.018 g, 44.8% yield) was prepared in a manner similar to the procedure described in Example 160. , 6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl) prepared as described in Intermediate 11 Pyrimidin-4-ol (0.019 g, 0.053 mmol), and (9R,13S)-13-amino-3-( ^2H3 )methyl-9-methyl-3,4, prepared as described in Intermediate ₃₃ , Use 7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.016 g, 0.053 mmol) It was manufactured. MS(ESI) m/z: 645.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.81 (d, J=0.7 Hz, 1H), 8.78 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 7.87 (dd, J=8.6, 7.7 Hz, 1H), 7.70 (s, 1H), 7.59 (dd, J=8.7, 1.4 Hz, 1H), 7.53 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.64 ( s, 1H), 6.00 (dd, J=12.7, 4.3 Hz, 1H), 2.75 - 2.65 (m, 1H), 2.33 - 2.22 (m, 1H), 2.12 - 1.92 (m, 2H), 1.66 - 1.40 ( m, 2H), 1.00 (d, J=6.8 Hz, 3H), 0.78 - 0.60 (m, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -62.59 (s), -77.76 (s), -114.95 (s). Analytical HPLC (Method A): RT = 8.44 min, 100% purity; Factor XIa Ki = 0.11 nM, plasma kallikrein Ki = 12 nM.

Example 176

1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl} Preparation of -3-fluorophenyl)-1H-1,2,3-triazole-4-carbonitrile trifluoroacetate

1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl} -3-Fluorophenyl)-1H-1,2,3-triazole-4-carbonitrile trifluoroacetate (9 mg, 20.1% yield) was prepared as described in Intermediate 12 in a manner similar to the procedure described in Example 160. 1-(4-Chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-1,2,3-triazole-4-carbonitrile (18.89 mg, 0.060 mmol), and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo prepared as described in Intermediate 30. [12.3.1.0 ^2,6 ] Octadeca-1(18),2(6),4,14,16-pentaen-8-one (20 mg, 0.060 mmol) was used. MS(ESI) m/z: 635.2 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.92 (s, 1H), 8.81 (s, 1H), 8.77 (d, J=5.3 Hz, 1H), 7.92 - 7.85 (m, 1H), 7.81 - 7.48 ( m, 5H), 6.65 (s, 1H), 6.00 (dd, J=12.7, 4.5 Hz, 1H), 2.76 - 2.65 (m, 1H), 2.34 - 2.22 (m, 1H), 2.10 - 1.95 (m, 2H), 1.64 - 1.41 (m, 2H), 0.99 (d, J=6.8 Hz, 3H), 0.73 - 0.55 (m, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -77.28 (s), -90.87 - -92.15 (m), -96.05 - -97.42 (m), -114.86 (s). Analytical HPLC (Method A): RT = 9.02 min, 99.6% purity; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 7 nM.

Example 177

(9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo -1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca -Preparation of 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[3-chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo -1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (7.07 mg, 20.6% yield) was prepared as described in Intermediate 14 in a manner similar to the procedure described in Example 160. 6-(3-Chloro-6-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2-fluorophenyl) pyrimidin-4-ol (0.015 g , 0.045 mmol), and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[ 12.3.1.0 ^2,6 ] prepared using octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.015 g, 0.045 mmol). MS(ESI) m/z: 650.5 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.92 (s, 1H), 8.76 (d, J=5.1 Hz, 1H), 7.86 - 7.47 (m, 7H), 6.50 (s, 1H), 6.04 (dd, J=12.5, 4.4 Hz, 1H), 2.77 - 2.66 (m, 1H), 2.35 - 2.24 (m, 1H), 2.10 - 1.87 (m, 3H), 1.66 - 1.41 (m, 2H), 1.02 - 0.89 ( m, 5H), 0.73 - 0.50 (m, 3H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -77.68 (s), -90.26 - -91.77 (m), -95.81 - -97.73 (m), -115.24 (s). Analytical HPLC (Method A): RT = 8.74 min, 99.8% purity; Factor XIa Ki = 0.50 nM, plasma kallikrein Ki = 120 nM.

Example 178

(9R,13S)-13-(4-{3-chloro-6-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]-2-fluorophenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ] Preparation of octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{3-chloro-6-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]-2-fluorophenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (0.016 g, 46.0% yield) was prepared in a manner similar to the procedure described in Example 160. 6-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyri prepared as described in Intermediate 21 Mydin-4-ol (0.015 g, 0.045 mmol), and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7 prepared as described in Intermediate 30. Using ,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (15 mg, 0.045 mmol) Manufactured. MS(ESI) m/z: 660.5 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.86 (s, 1H), 8.73 (d, J=5.1 Hz, 1H), 8.52 (t, J=1.4 Hz, 1H), 7.86 (dd, J=8.6, 7.5 Hz, 1H), 7.80 - 7.48 (m, 5H), 6.96 (t, J=54.0 Hz, 1H), 6.60 (s, 1H), 6.02 (dd, J=12.5, 4.4 Hz, 1H), 2.76 - 2.66 (m, 1H), 2.32 - 2.20 (m, 1H), 2.09 - 1.92 (m, 2H), 1.65 - 1.40 (m, 2H), 0.99 (d, J=7.0 Hz, 3H), 0.69 - 0.52 ( m, 1H). ¹⁹ F NMR (376MHz, CD ₃ OD) δ -77.73 (s), -90.24 - -92.35 (m), -95.39 - -97.64 (m), -114.57 (d, J=10.3 Hz), -115.06 (s) ). Analytical HPLC (Method A): RT = 8.91 min, 99.6% purity; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 16 nM.

Example 179

(9R,13S)-13-(4-{3-chloro-6-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]-2-fluorophenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( Preparation of 18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{3-chloro-6-[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]-2-fluorophenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-8-one trifluoroacetate (0.015 g, 43.3% yield) was prepared as described in Intermediate 21 in a manner similar to the procedure described in Example 160. 6-(3-chloro-6-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol (0.016 g, 0.047 mmol), and (9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 prepared as described in Intermediate 32. ]Prepared using octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.014 g, 0.047 mmol). MS(ESI) m/z: 624.5 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.79 (s, 1H), 8.72 (d, J=5.1 Hz, 1H), 8.52 (t, J=1.3 Hz, 1H), 7.86 (dd, J=8.6, 7.7 Hz, 1H), 7.70 (s, 1H), 7.59 - 7.51 (m, 2H), 7.48 (s, 1H), 6.97 (t, J=54.0 Hz, 1H), 6.60 (s, 1H), 5.99 ( dd, J=12.7, 4.3 Hz, 1H), 4.05 (s, 3H), 2.75 - 2.64 (m, 1H), 2.34 - 2.21 (m, 1H), 2.12 - 1.93 (m, 2H), 1.66 - 1.39 ( m, 2H), 1.00 (d, J=6.8 Hz, 3H), 0.78 - 0.59 (m, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -77.74 (s), -114.52 (d, J=8.0 Hz), -115.03 (s). Analytical HPLC (Method A): RT = 7.79 min, 99.6% purity; Factor XIa Ki = 0.14 nM, plasma kallikrein Ki = 16 nM.

Example 180

(9R,13S)-13-[4-(3-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15- Preparation of tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(3-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15- Tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (3.35 mg, 15% yield) Pyridin-3-ylboronic acid (4.76 mg, 0.039 mmol) was reacted with lithium 4-methyl-1-(1-methyl-1H-1,2,3-triazol-4-yl) in a manner similar to the procedure described in Example 161. )-2,6,7-trioxa-1-borabicyclo [2.2.2]octane-1-oid (8.41 mg, 0.039 mmol) was substituted for it. MS(ESI) m/z: 489.3 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 9.01 (s, 1H), 8.73 (d, J=5.2 Hz, 1H), 8.08 (t, J=1.7 Hz, 1H), 7.94 (dt, J=7.5, 1.6 Hz, 1H), 7.73 (s, 1H), 7.54 - 7.44 (m, 4H), 6.93 (d, J=0.5 Hz, 1H), 6.04 (dd, J=12.5, 4.0 Hz, 1H), 4.05 ( s, 3H), 2.76 - 2.68 (m, 1H), 2.42 - 2.32 (m, 1H), 2.15 - 2.02 (m, 2H), 1.67 - 1.57 (m, 1H), 1.55 - 1.45 (m, 1H), 1.02 (d, J=6.9 Hz, 3H), 0.81 - 0.65 (m, 1H). Analytical HPLC (Method A): RT = 7.33 min, 99.0% purity; Factor XIa Ki = 360 nM, plasma kallikrein Ki = 6,800 nM.

Example 181

4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1 (18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}Preparation of benzoic acid

Methyl 4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7 prepared as described in Example 168 in DCM (0.5 ml) at 0°C ,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6- To a solution of dihydropyrimidin-4-yl}benzoate trifluoroacetate (0.02 g, 0.030 mmol) was added BBr ₃ (0.029 ml, 0.30 mmol). The reaction became a yellow suspension. After 10 minutes, the cooling bath was removed and the reaction was stirred at room temperature. After 18 hours, the reaction was cooled to 0° C. and carefully quenched with MeOH. The reaction was warmed to room temperature and then concentrated. Purified by reverse phase chromatography, 4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}benzoic acid trifluo Roacetate (0.011 g, 56% yield) was obtained as a white solid. MS(ESI) m/z: 533.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.00 (s, 1H), 8.74 (d, J=5.1 Hz, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.73 (s, 1H), 7.61 - 7.56 (m, 2H), 7.53 (dd, J=5.3, 1.5 Hz, 1H), 7.50 (s, 1H), 6.58 (s, 1H), 6.07 (dd, J=12.8, 4.2 Hz, 1H), 4.05 (s, 3H), 2.77 - 2.67 (m, 1H), 2.41 - 2.30 (m, 1H), 2.16 - 2.00 (m, 2H), 1.68 - 1.57 (m, 1H), 1.55 - 1.43 (m, 1H) ), 1.01 (d, J=7.0 Hz, 3H), 0.79 - 0.62 (m, 1H). Analytical HPLC (Method A): RT = 5.54 min, 99.9% purity; Factor XIa Ki = 500 nM.

Example 182

(9R,13S)-3-(difluoromethyl)-9-methyl-13-{6-oxo-4-[5-(propan-2-yl)-2-[4-(trifluoromethyl) -1H-1,2,3-triazol-1-yl]phenyl]-1,6-dihydropyrimidin-1-yl}-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]Preparation of octadeca-1(18),2(6),4,14,16-pentaen-8-one

182A. Preparation of 4-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

4-Isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.21 g, 99%) was reacted with 2-bromo-4- Prepared in a similar manner to Example 119A, starting from isopropylaniline. MS(ESI) m/z: 180 (MC ₆ H ₁₀ +H) ⁺ .

182B. Preparation of 4-isopropyl-2-(6-methoxypyrimidin-4-yl)aniline

4-Isopropyl-2-(6-methoxypyrimidin-4-yl)aniline (511 mg, 46%) was reacted with 4-isopropyl-2-(4,4,5,5) in a manner similar to Example 119B. It was prepared using -tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. MS(ESI) m/z: 244.1 (M+H) ⁺ .

182C. Preparation of 4-(5-isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine

4-(5-isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine (522 mg, 68% ) was prepared using 4-isopropyl-2-(6-methoxypyrimidin-4-yl)aniline in a manner similar to Example 119C. MS(ESI) m/z: 364.1 (M+H) ⁺ .

182D. Preparation of 6-(5-isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

6-(5-isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (459 mg, 91%) 4-(5-isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxyp in a similar manner to Example 119D. It was prepared using limidine. MS(ESI) m/z: 350.1 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 12.53 (br. s., 1H), 8.06 (s, 1H), 7.92 (s, 1H), 7.58 - 7.50 (m, 2H), 7.47 - 7.44 (m, 1H) ), 6.54 (s, 1H), 3.15 - 3.03 (m, 1H), 1.38 - 1.30 (m, 6H).

182E. (9R,13S)-3-(difluoromethyl)-9-methyl-13-{6-oxo-4-[5-(propan-2-yl)-2-[4-(trifluoromethyl) -1H-1,2,3-triazol-1-yl]phenyl]-1,6-dihydropyrimidin-1-yl}-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]Octadeca-1(18),2(6),4,14,16-pentaen-8-one, production of trifluoroacetate

(9R,13S)-3-(difluoromethyl)-9-methyl-13-{6-oxo-4-[5-(propan-2-yl)-2-[4-(trifluoromethyl) -1H-1,2,3-triazol-1-yl]phenyl]-1,6-dihydropyrimidin-1-yl}-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one, trifluoroacetate (1.6 mg, 3.4%) was prepared as Intermediate 30 in a similar manner to Example 56. 6-(5-isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol ( 21 mg, 0.060 mmol) and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ] It was prepared using octadeca-1(18),2(6),4,14,16-pentaen-8-one (20 mg, 0.060 mmol). MS(ESI) m/z: 668.2 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 9.17 (s, 1H), 8.76 (s, 1H), 8.70 (d, J=5.2 Hz, 1H), 8.09 - 7.94 (m , 1H), 7.91 - 7.80 (m, 1H), 7.73 - 7.60 (m, 3H), 7.43 (d, J=4.7 Hz, 1H), 6.39 (s, 1H), 5.90 (d, J=10.2 Hz, 1H), 3.09 (dt, J=13.9, 6.8 Hz, 1H), 2.64 (d, J=3.3 Hz, 1H), 2.29 (t, J=12.7 Hz, 1H), 2.09 - 2.01 (m, 1H), 1.87 - 1.80 (m, 1H), 1.52 - 1.43 (m, 1H), 1.30 (d, J=6.9 Hz, 5H), 0.87 (d, J=6.9 Hz, 2H), 0.37 (br. s., 1H) ). Analytical HPLC (Method C): RT = 2.00 min, 100% purity; Factor XIa Ki = 500 nM.

Example 183

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-( ^2H3 )methyl-9-methyl-3,4,7,17 _- tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6 as a white solid. -Oxo-1,6-dihydropyrimidin _- 1-yl)-3-( ^2H3 )methyl-9-methyl-3,4,7,17-tetraazatricyclo [12.3.1.0 ^2,6 ] Octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.068 g, 18.7%) was reacted with 6 as described in Intermediate 15 in a manner similar to the procedure described in Example 56. -(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (0.188 g, 0.549 mmol), and (9R, _13S )-13-amino-3-( ^2H3 )methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ]octa as described in Intermediate 34 It was prepared using deca-1(18),2(6),4,14,16-pentaen-8-one (0.166 g, 0.549 mmol). MS(ESI) m/z: 627.5 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.84 (d, J=0.7 Hz, 1H), 8.72 (d, J=5.1 Hz, 1H), 8.29 (s, 1H), 7.91 (d, J=2.4 Hz) , 1H), 7.86 (s, 1H), 7.82 - 7.76 (m, 1H), 7.74 - 7.69 (m, 1H), 7.51 (s, 1H), 7.16 (dd, J=5.2, 1.7 Hz, 1H), 6.53 (d, J=0.9 Hz, 1H), 5.78 (dd, J=12.4, 3.0 Hz, 1H), 2.70 - 2.57 (m, 1H), 2.40 (d, J=12.8 Hz, 1H), 2.15 - 2.08 (m, 1H), 2.04 - 1.94 (m, 1H), 1.64 (d, J=6.8 Hz, 1H), 1.48 - 1.32 (m, 2H), 1.15 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT = 8.04 min, purity = 95%; Factor XIa Ki = 0.15 nM, plasma kallikrein Ki = 18 nM.

Example 184

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,14,16-pentaene-16-carbonitrile

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6 as a white solid. -Oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo [12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaene-16-carbonitrile (8 mg, 13.5%) was reacted with (9R,13S)-13 as described in Example 130. -{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl }-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl] pyrimidine in a similar manner to 4,14,16-pentaene-16-carbonitrile -4-ol was reacted with 6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidine- as described in Intermediate 15. It was prepared by replacing it with 4-ol. LCMS (ESI) m/z: 684.2 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.82 (d, J=0.7 Hz, 1H), 8.32 (s, 1H), 8.03 (s, 1H), 7.90 (d, J=2.4 Hz, 2H), 7.83 - 7.75 (m, 3H), 7.73 - 7.43 (m, 2H), 6.48 (d, J=0.4 Hz, 1H), 5.76 (dd, J=13.1, 3.4 Hz, 1H), 2.60 - 2.42 (m, 2H) ), 2.17 - 2.05 (m, 1H), 1.88 (dt, J=7.2, 3.7 Hz, 1H), 1.64 - 1.53 (m, 1H), 1.42 (d, J=8.1 Hz, 1H), 1.20 (br. s., 1H), 1.13 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT = 9.31 min, purity = 98%; Factor XIa Ki = 0.10 nM, plasma kallikrein Ki = 15 nM.

Example 185

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,17-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6 as a white solid. -Oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1 (18) ,2(6),4,14,16-pentaen-8-one (0.16 g, 27%) was reacted with 6-(5-chloro-2-(4) as described in Intermediate 15 in a manner similar to Example 56. -(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (0.308 g, 0.902 mmol), and (9R,13S as described in Intermediate 42 )-13-amino-3,9-dimethyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16 -Prepared using pentaen-8-one (0.27 g, 0.902 mmol). LCMS (ESI) m/z: 624.5 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.84 (d, J=0.9 Hz, 1H), 8.71 (d, J=5.5 Hz, 1H), 8.29 (s, 1H), 7.91 (d, J=2.2 Hz) , 1H), 7.86 (s, 1H), 7.80 - 7.75 (m, 1H), 7.73 - 7.70 (m, 1H), 7.51 (s, 1H), 7.16 (dd, J=5.2, 1.7 Hz, 1H), 6.53 (d, J=0.7 Hz, 1H), 5.78 (dd, J=12.5, 3.1 Hz, 1H), 4.18 (s, 3H), 2.69 - 2.55 (m, 1H), 2.40 (d, J=11.9 Hz) , 1H), 2.11 (dd, J=13.3, 3.6 Hz, 1H), 2.00 (dd, J=14.0, 3.6 Hz, 1H), 1.64 (d, J=7.0 Hz, 1H), 1.50 - 1.29 (m, 2H), 1.15 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT = 8.07 min, purity = 95%; Factor XIa Ki = 0.14 nM, plasma kallikrein Ki = 18 nM.

Example 186

(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one trifluoroacetate

186A. tert-Butyl N-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,14,16-pentaen-13-yl]carbamate

Fe ₂ (C ₂ O ₄ ) ₃ .6H ₂ O (1.910 g, 3.95 mmol) was dissolved in water (75 mL) and then purged with Ar (3x). Selectfluor® (1398 mg, 3.95 mmol) was added followed by tert-butyl N-[(9R,10E,13S)-3,9-dimethyl-8 prepared as described in Intermediate 32 in ACN (75 mL). -Oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl ] Carbamate (523 mg, 1.32 mmol) was added. NaBH ₄ (398 mg, 10.53 mmol) was added in portions, and the solution was stirred at room temperature for 1 hour. The reaction mixture was quenched with 30% aqueous NH ₄ OH (40 ml) and extracted with 500 ml 10% MeOH in DCM. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and concentrated. The residue was purified by reverse phase chromatography to obtain tert-butyl N-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[ 12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate and tert-butyl N-[(9R,13S)-11 -Fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14 A mixture of ,16-pentaen-13-yl]carbamates (130 mg) was obtained as a solid. Further purification by chiral reversed-phase chromatography yielded tert-butyl N-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo as the single isomer. [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (59 mg, 10% yield) was obtained as a white solid. did.

186B. (9S,13S)-13-amino-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2 Preparation of (6),4,14,16-pentaen-8-one

tert-Butyl N-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ² in DCM (2 mL) ^,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]TFA (0.709 mL, 9.20 mmol) in a solution of carbamate (96 mg, 0.230 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated to (9S,13S)-13-amino-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3. 1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate was obtained as a light yellow solid, which was then dissolved in MeOH and 6 500 mg of PL-HCO ₃ MP SPE per ml tube was passed through and rinsed with MeOH. The filtrate was concentrated to (9S,13S)-13-amino-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18),2(6),4,14,16-pentaen-8-one (72 mg, 99% yield) was obtained. MS(ESI) m/z: 318.08 (M+H) ⁺ .

186C. (9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one trifluoroacetate

((9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6- dihydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2 (6),4,14,16-pentaen-8-one) trifluoroacetate (7.7 mg, 39% yield) was purified from methyl (10R,14S)-14- in a manner similar to the procedure described in Example 184. Amino-10-methyl-9-oxo-8,16-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15,17-hexaene- 4-Carboxylate was reacted with (9S,13S)-13-amino-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- It was prepared by replacing it with 1(18),2(6),4,14,16-pentaen-8-one. MS(ESI) m/z: 608.08 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.77 (d, J=5.3 Hz, 1H), 8.36 (s, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.78 - 7.73 (m, 1H), 7.69 - 7.64 (m, 1H), 7.56 (d, J=0.9 Hz, 1H), 7.53 - 7.46 (m, 2H), 6.39 (d, J=0.7 Hz, 1H), 6.25 (dd, J=12.1, 5.9 Hz, 1H), 5.46 - 5.23 (m, 1H), 4.05 (s, 3H), 3.22 - 3.11 (m, 1H), 2.36 - 2.19 (m, 2H), 1.86 - 1.68 (m, 1H), 1.00 (d, J=6.8 Hz, 3H), 0.75 - 0.51 (m, 1H) Analytical HPLC (Method A): RT = 8.33 min, purity = >97%; Factor XIa Ki = 0.37 nM, plasma kallikrein Ki = 30 nM.

Example 187

(9R,13S)-3-(difluoromethyl)-13-(4-{5-ethyl-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1- yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,14,16-pentaen-8-one

187A. Preparation of 4-ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

4-Ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.638 g, 52%) was reacted with 2 in a similar manner to Example 119A. -Prepared starting from bromo-4-ethylaniline. MS(ESI) m/z: 166.0 (MC ₆ H ₁₀ +H) ⁺ .

¹ H NMR (400MHz, chloroform-d) δ 7.44 (d, J=2.2 Hz, 1H), 7.08 (dd, J=8.3, 2.3 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 4.60 (br. s., 2H), 1.38 - 1.33 (m, 12H), 1.27 (s, 2H), 1.21 - 1.16 (m, 3H).

187B. Preparation of 4-ethyl-2-(6-methoxypyrimidin-4-yl)aniline

4-Ethyl-2-(6-methoxypyrimidin-4-yl)aniline (611 mg, 60%) was reacted with 4-ethyl-2-(4,4,5,5-tetra) in a manner similar to Example 119B. It was prepared using methyl-1,3,2-dioxaborolan-2-yl)aniline. MS(ESI) m/z: 230.1 (M+H) ⁺ .

187C. Preparation of 4-(5-ethyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine

4-(5-ethyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine (430 mg, 46%) was prepared using 4-ethyl-2-(6-methoxypyrimidin-4-yl)aniline in a similar manner to Example 119C. MS(ESI) m/z: 350.1 (M+H) ⁺ .

187D. Preparation of 6-(5-isopropyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

6-(5-ethyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (345 mg, 84%) 4-(5-ethyl-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine in a similar manner to Example 119D It was manufactured using. MS(ESI) m/z: 336.1 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 12.80 (br. s., 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.59 - 7.41 (m, 3H), 6.53 (s, 1H), 2.83 (q, J=7.7 Hz, 2H), 1.34 (t, J=7.6 Hz, 3H).

187E. (9R,13S)-3-(difluoromethyl)-13-(4-{5-ethyl-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1- yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-3-(difluoromethyl)-13-(4-{5-ethyl-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1- yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (0.9 mg, 2.0%) was reacted with 6-(5-ethyl-2-) in a manner similar to Example 56. (4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (21 mg, 0.060 mmol) and (prepared as described in Intermediate 30 9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18), It was prepared using 2(6),4,14,16-pentaen-8-one (20 mg, 0.060 mmol). MS(ESI) m/z: 654.2 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.40 (s, 1H), 9.18 (s, 1H), 8.78 - 8.65 (m, 2H), 8.09 - 7.93 (m, 1H), 7.90 - 7.83 (m, 1H), 7.72 - 7.65 (m, 3H), 7.59 (dd, J=8.2, 1.5 Hz, 1H), 7.43 (d, J=4.9 Hz, 1H), 6.38 (s, 1H), 5.90 (d, J =9.5 Hz, 1H), 2.79 (q, J=7.4 Hz, 2H), 2.69 - 2.61 (m, 1H), 2.28 (t, J=12.5 Hz, 1H), 2.09 - 2.00 (m, 1H), 1.89 - 1.79 (m, 1H), 1.47 (dt, J=12.2, 6.4 Hz, 1H), 1.38 - 1.23 (m, 4H), 0.88 (d, J=6.7 Hz, 3H), 0.36 (br. s., 1H). Analytical HPLC (Method C): RT = 1.896 min, 100% purity; Factor XIa Ki = 110 nM.

Example 188

(9S,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( Preparation of 18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9S,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1( 18),2(6),4,14,16-pentaen-8-one (9.33 mg, 32% yield) was purified from 6-[5-chloro-2-(4) in a manner similar to the procedure described in Example 186. -Chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol was reacted with 6-[3-chloro-6-(4-chloro-1H) prepared as described in Intermediate 10. It was prepared by replacing -1,2,3-triazol-1-yl)-2-fluorophenyl]pyrimidin-4-ol. MS(ESI) m/z: 626.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.78 (d, J=5.1 Hz, 1H), 8.34 (s, 1H), 7.88 (dd, J=8.7, 7.6 Hz, 1H) , 7.60 - 7.54 (m, 2H), 7.53 - 7.48 (m, 2H), 6.63 (s, 1H), 6.27 (dd, J=11.8, 6.3 Hz, 1H), 5.44 - 5.25 (m, 1H), 4.05 (s, 3H), 3.23 - 3.12 (m, 1H), 2.35 - 2.21 (m, 2H), 1.85 - 1.69 (m, 1H), 1.00 (d, J=6.8 Hz, 3H), 0.75 - 0.52 (m , 1H). Analytical HPLC (Method A): RT = 8.41 min, purity = >99%; Factor XIa Ki = 0.15 nM, plasma kallikrein Ki = 19 nM.

Example 189

(9R,13S)-13-{5-chloro-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1 ,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), 4,14,16-pentaen-8-one trifluoroacetate production

189A. Preparation of 5-chloro-6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol.

6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidine-4- prepared as described in Intermediate 9 in ACN (3.24 mL) To a solution of ol (100 mg, 0.325 mmol) was added Palau'chlor (82 mg, 0.389 mmol). The reaction was stirred at 60° C. for 4 hours, then the reaction was cooled to room temperature and concentrated. Purification by normal phase chromatography using EtOAc/Hex gave a white solid weighing 0.135 g. Purification by reverse phase chromatography gave a white solid. The solid was partitioned between saturated NaHCO ₃ and EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc. The organic layers were combined, dried over MgSO ₄ , filtered and concentrated to give 5-chloro-6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl. ] Pyrimidin-4-ol (63 mg, 57%) was obtained as a beige solid. MS(ESI) m/z: 342 (M+H) ⁺ , 344.1 (M+2+H) ⁺ , and 346.0 (M+4+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.09 (s, 1H), 7.75 (s, 1H), 7.66 - 7.61 (m, 2H), 7.55 - 7.50 (m, 1H).

189B. (9R,13S)-13-{5-chloro-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1 ,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), 4,14,16-pentaen-8-one trifluoroacetate production

(9R,13S)-13-{5-chloro-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1 ,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6) ), 4,14,16-pentaen-8-one trifluoroacetate (0.0071 g, 23%) was reacted with 6-{5-chloro-2-[4-(tri fluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol to 5-chloro-6-[5-chloro-2-(4-chloro-1H-1 , 2,3-triazol-1-yl) phenyl] pyrimidin-4-ol. MS(ESI) m/z: 624 (M+H) ⁺ , 626.3 (M+2+H) ⁺ , and 628.2 (M+4+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.15 (s, 1H), 8.83 (s, 1H), 8.75 (s, 1H), 8.63 (d, J=5.0 Hz, 1H), 7.83 - 7.73 (m , 3H), 7.62 (s, 1H), 7.53 (dd, J=5.1, 1.5 Hz, 1H), 7.40 (s, 1H), 5.88 - 5.78 (m, 1H), 3.95 (s, 3H), 2.62 - 2.52 (m, 1H), 2.32 - 2.21 (m, 1H), 2.08 - 1.98 (m, 1H), 1.87 - 1.78 (m, 1H), 1.47 - 1.36 (m, 1H), 1.33 - 1.21 (m, 1H) ), 0.81 (d, J=6.9 Hz, 3H), 0.45 - 0.29 (m, 1H). Analytical HPLC (Method A): RT = 8.03 min, purity = 99.5%; Factor XIa Ki = 0.46 nM, plasma kallikrein Ki = 29 nM.

Example 190

(9R,13S)-3-(difluoromethyl)-13-(4-{4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1 -yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca -Preparation of 1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-3-(difluoromethyl)-13-(4-{4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1 -yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca -1(18),2(6),4,14,16-pentaen-8-one was reacted with (6-{4-fluoro-2) using the HATU, DBU coupling methodology as described in Example 56. -[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (0.006 g, 0.018 mmol) and (9R,13S)-13- Amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4, Prepared as a solid (0.72 mg, 6% yield) via coupling of 14,16-pentaen-8-one (0.006 g, 0.018 mmol) by LCMS m/z = 644.2 (M+H) ⁺ .

^1H NMR (400MHz, CD ₃ OD) δ 8.83 - 8.77 (m, 2H), 8.73 - 8.69 (m, 1H), 7.91 - 7.86 (m, 1H), 7.75 - 7.72 (m, 2H), 7.68 - 7.49 (m, 4H), 6.05 - 5.96 (m, 1H), 2.75 - 2.62 (m, 1H), 2.30 - 2.18 (m, 1H), 2.05 - 1.94 (m, 2H), 1.64 - 1.36 (d, 3H) , 1.02 - 0.94 (m, 1H). Analytical HPLC (Method A) RT = 8.75 min, purity = 98%; Factor XIa Ki = 110 nM.

Example 191

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-( ^2H3 )methyl-9 _- methyl-3,4,7,17-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), Preparation of 2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1 as a white solid, 6-dihydropyrimidin-1-yl}-3-( ^2H3 )methyl-9-methyl-3,4,7,17 _- tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1( 18),2(6),4,14,16-pentaen-8-one (10.8 mg, 18.4%) was reacted with 6-[5-chloro-2- as described in Intermediate 9 in a manner similar to Example 56. (4-chloro-1H-1,2,3-triazol-1-yl)phenyl] pyrimidin-4-ol (0.024 g, 0.079 mmol), and (9R,13S)-13 as described in Intermediate 34 -Amino-3-( ^2H3 )methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 _] octadeca-1(18),2(6),4 ,14,16-pentaen-8-one (0.024 g, 0.079 mmol) was used. LCMS (ESI) m/z: 593.3 (M+H) ⁺ .

^1H NMR (400MHz, CD ₃ OD) δ 8.78 - 8.69 (m, 1H), 8.42 - 8.33 (m, 2H), 7.92 - 7.86 (m, 2H), 7.80 - 7.74 (m, 1H), 7.69 - 7.64 (m, 1H), 7.52 (s, 1H), 7.21 (dd, J=5.3, 1.5 Hz, 1H), 6.51 - 6.43 (m, 1H), 5.77 (dd, J=12.5, 3.3 Hz, 1H), 2.62 (ddd, J=9.5, 6.7, 3.4 Hz, 1H), 2.48 - 2.38 (m, 1H), 2.22 - 2.11 (m, 1H), 2.06 - 1.97 (m, 1H), 1.69 - 1.59 (m, 1H) ), 1.42 - 1.33 (m, 2H), 1.15 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A) RT = 7.77 min, purity = 96%; Factor XIa Ki = 0.19 nM, plasma kallikrein Ki = 22 nM.

Example 192

(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoro Methyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8 -manufacture of

192A. Preparation of 6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol

6-(3-Chloro-2,6-difluorophenyl)pyrimidin-4-ol hydrobromide prepared as described in Intermediate 4 was partitioned between EtOAc and saturated NaHCO ₃ . The layers were separated and the organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a white solid. The solid was suspended in Et ₂ O and sonicated. The solid was collected by filtration, rinsed with Et ₂ O and dried under vacuum to give 6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol as a white solid. MS(ESI) m/z: 243.0 (M+H) ⁺ and 245.0 (M+2+H) ⁺ .

192B. (9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoro methyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaene-8 -manufacture of

(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoro Methyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8 -one trifluoroacetate (0.0092 g, 30%) was added to 6-(3-chloro-2,6-difluorophenyl)pyrimidin-4-ol (10.8 mg, 0.045 mmol) and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo prepared as described in Intermediate 30 [12.3. It was prepared using 1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.015 g, 0.045 mmol). MS(ESI) m/z: 561.1 (M+H) ⁺ and 563.1 (M+2+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 9.09 (s, 1H), 8.77 (d, J=5.0 Hz, 1H), 7.79 - 7.72 (m, 2.25H), 7.67 - 7.60 (m, 1.5H), 7.56 - 7.52 (m, 1.25H), 7.14 (dt, J=9.1, 1.9 Hz, 1H), 6.67 (s, 1H), 6.11 - 6.04 (m, 1H), 2.76 - 2.69 (m, 1H), 2.42 - 2.33 (m, 1H), 2.13 - 2.02 (m, 2H), 1.66 - 1.56 (m, 1H), 1.56 - 1.46 (m, 1H), 1.01 (d, J=6.9 Hz, 3H), 0.73 - 0.60 (m, 1H). ¹⁹ F NMR (471 MHz, CD ₃ OD) δ -114.75 (d, J=4.3 Hz), -115.47 (d, J=4.3 Hz), -77.66 (s). Analytical HPLC (Method A): RT = 8.38 min, purity = 99.7%; Factor XIa Ki = 30 nM, plasma kallikrein Ki = 670 nM.

Example 193

(9R,13S)-13-[4-(5-chloro-2-phenylphenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4, Preparation of 7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(5-chloro-2-phenylphenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4, 7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (5 mg, 21 % yield) was prepared in a manner similar to the procedure described in Example 161, replacing pyridin-3-ylboronic acid (4.76 mg, 0.039 mmol) with phenylboronic acid (4.72 mg, 0.039 mmol). MS(ESI) m/z: 565.4 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.92 (s, 1H), 8.72 (d, J=5.0 Hz, 1H), 7.71 (d, J=2.2 Hz, 1H), 7.66 (s, 1H), 7.55 - 7.50 (m, 2H), 7.48 (s, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.34 - 7.26 (m, 3H), 7.24 - 7.20 (m, 2H), 6.08 (d, J =0.8 Hz, 1H), 5.94 (dd, J=12.5, 4.0 Hz, 1H), 4.04 (s, 3H), 2.73 - 2.65 (m, 1H), 2.34 - 2.24 (m, 1H), 2.10 - 1.94 ( m, 2H), 1.63 - 1.54 (m, 1H), 1.52 - 1.41 (m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.74 - 0.59 (m, 1H). Analytical HPLC (Method A): RT = 12.43 min, 98.2% purity; Factor XIa Ki = 160 nM, plasma kallikrein Ki = 4,700 nM.

Example 194

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (5 mg, 4.9%) was prepared as described in Intermediate 15 in a manner similar to Example 56. {5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol, and prepared as described in Intermediate 43 (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,16-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18) It was prepared using ,2(6),4,14,16-pentaen-8-one. MS(ESI) m/z: 660.2 (M+H) ⁺ .

^1H NMR (400MHz, methanol-d4) δ 8.84 (d, J=0.7 Hz, 1H), 8.78 (s, 1H), 8.65 (d, J=2.0 Hz, 1H), 8.34 (s, 1H), 8.27 (t, J=1.9 Hz, 1H), 7.92 (d, J=2.2 Hz, 1H), 7.82 - 7.77 (m, 2H), 7.73 - 7.70 (m, 1H), 6.50 (d, J=0.7 Hz, 1H), 5.79 (dd, J=12.9, 3.4 Hz, 1H), 2.58 - 2.48 (m, 2H), 2.22 - 2.14 (m, 1H), 1.92 - 1.87 (m, 1H), 1.64 - 1.57 (m, 2H), 1.17 (d, J=6.8 Hz, 3H), 1.12 - 1.03 (m, 1H). Analytical HPLC (Method A): RT = 8.10 min, purity = 90%; Factor XIa Ki = 0.13 nM, plasma kallikrein Ki = 66 nM.

Example 195

(9R,13S)-13-[4-(5-chloro-1-ethyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3- (difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2, 6]octadeca-1(18),2(6),4,14,16- Preparation of pentaen-8-one

195A. Preparation of 6-(5-chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol

6-(5-Chloro-1-methyl-1H-indazol-7-yl)pyrimidin-4-ol was prepared in a similar manner as intermediate 22 by replacing MeI with EtI. MS(ESI) m/z: 275.1 (M+H) ⁺ and 277.1 (M+2+H) ⁺ .

195B. (9R,13S)-13-[4-(5-chloro-1-ethyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3- (difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16- Preparation of pentaen-8-one trifluoroacetate

(9R,13S)-13-[4-(5-chloro-1-ethyl-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3- (difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16- Pentaen-8-one, trifluoroacetate (10.8 mg, 25%) was reacted with 6-(5-chloro-1-methyl-1H-indazol-7-yl)pyrimidine-4 in a manner similar to Example 56. -ol and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0] prepared as described in Intermediate 30 ^2,6 ]Octadeca-1(18),2(6),4,14,16-pentaen-8-one was used to prepare it. MS(ESI) m/z: 593.2 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.12 (s, 1H), 8.76 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.83 - 7.73 (m, 2H), 7.69 - 7.50 (m, 2H), 7.45 - 7.41 (m, 1H), 6.73 (s, 1H), 6.12 (dd, J=12.9, 4.3 Hz, 1H), 4.39 - 4.26 (m, 2H), 2.77 - 2.72 (m, 1H), 2.44 - 2.35 (m, 1H), 2.14 - 2.05 (m, 2H), 1.65 - 1.50 (m, 2H), 1.23 (t, J=7.2 Hz) , 3H), 1.01 (d, J=7.0 Hz, 2H), 0.67 (br. s., 1H). Analytical HPLC (Method A): RT = 8.69 min, purity = >99%; Factor XIa Ki = 110 nM, plasma kallikrein Ki = 8,400 nM.

Example 196

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) , Preparation of 4,14,16-pentaen-8-one

196A. (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-9-methyl-3-{[2-(trimethylsilyl)ethoxy] methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0 Preparation of ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (760 mg, 0.975 mmol, 74% yield) was prepared in a manner similar to the procedure described in Example 56. 6-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidine-4- prepared as described in Intermediate 15. ol (0.452 g, 1.323 mmol), and (9R,13S)-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7, prepared as described in Intermediate 19, Prepared using 15-tetraazatricyclo [12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.550 g, 1.323 mmol) did. MS(ESI) m/z: 740.6 [M+H] ⁺ .

196B. (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) , Preparation of 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl in DCM (4.0 mL) }-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraaza To a solution of tricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (760 mg, 1.027 mmol) was added TFA (1.0 mL, 12.98 mmol) was added, and the resulting solution was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated and the residue was purified by preparative HPLC purification to give (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1 ,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[ 12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (480 mg, 92% yield) was obtained.

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.26 (s, 1H), 9.21 (s, 1H), 8.63 (br. s., 1H), 8.49 (br. s., 1H), 7.96 (d, J=1.5 Hz, 1H), 7.87 - 7.78 (m, 2H), 7.47 (br. s., 1H), 7.24 - 6.98 (m, 1H), 6.48 (s, 1H), 5.97 (br. s., 1H), 3.45 - 3.36 (m, 2H), 2.72 (br. s., 1H), 2.32 - 2.15 (m, 2H), 1.80 (br. s., 1H), 1.52 (br. s., 1H) , 1.38 (br. s., 1H), 0.92 (d, J=6.7 Hz, 3H), 0.59 (br. s., 1H). MS(ESI) m/z: 610.1 [M+H] ⁺ . Analytical HPLC (Method B): RT = 1.57 min, purity = 97.0%; Factor XIa Ki = 1.9 nM, plasma kallikrein Ki = 205 nM.

Example 197

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1, 6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6) , Preparation of 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1, 6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6) , 4,14,16-pentaen-8-one trifluoroacetate (6.9 mg, 16% yield) was prepared as described in Intermediate 32 in a manner similar to the procedure described in Example 196 (9R,13S)- 13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-penta Prepared using en-8-one. MS(ESI) m/z: 575.2 (M+H) ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 9.46 (br. s., 1H), 8.76 (d, J=8.1 Hz, 2H), 7.91 (d, J=6.8 Hz, 1H), 7.80 (br. s) ., 1H), 7.62 (d, J=7.0 Hz, 2H), 7.53 (br. s., 1H), 6.70 (br. s., 1H), 5.95 (br. s., 1H), 4.09 (br. . s., 3H), 2.71 (br. s., 1H), 2.32 (br. s., 1H), 2.05 (br. s., 2H), 1.62 (br. s., 1H), 1.46 (br. s., 1H), 1.46 (br. s., 1H) . s., 1H), 1.03 (br. s., 3H), 0.77 (br. s., 1H) Analytical HPLC (Method A): RT = 6.71 min, purity = >99%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 8 nM.

Example 198

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1, 6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of 2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1, 6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1 (18) ,2(6),4,14,16-pentaen-8-one trifluoroacetate (9.7 mg, 33% yield) prepared as described in Intermediate 35 in a manner similar to the procedure described in Example 196 ( 9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2( 6), Prepared using 4,14,16-pentaen-8-one. MS(ESI) m/z: 610.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.42 (s, 1H), 8.17 (s, 1H), 7.89 (dd, J=8.7, 7.6 Hz, 1H), 7.81 - 7.75 (m, 2H), 7.65 - 7.46 (m, 4H), 7.38 (d, J=7.7 Hz, 1H), 6.71 (d, J=0.9 Hz, 1H), 5.81 (dd, J=12.9, 3.4 Hz, 1H), 2.56 - 2.44 (m , 1H), 2.40 - 2.25 (m, 1H), 2.17 - 2.05 (m, 1H), 1.94 - 1.82 (m, 1H), 1.63 - 1.47 (m, 2H), 1.27 - 1.17 (m, 1H), 1.15 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A): RT = 8.62 min, purity = >99%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 4 nM.

Example 199

(9R,13S)-13-{4-[5-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), Preparation of 2(6),4,14,16-pentaen-8-one

199A. Preparation of 6-(5-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)pyrimidin-4-ol

6-(5-Chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)pyrimidin-4-ol (25 mg, 62%) was prepared in a similar manner to intermediate 22. It was prepared by replacing MeI with 2-bromo-1,1,1-trifluoroethane. MS(ESI) m/z: 329 (M+H) ⁺ and 331 (M+2+H) ⁺ .

199B. (9R,13S)-13-{4-[5-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), Preparation of 2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), 2(6),4,14,16-pentaen-8-one trifluoroacetate (14.5 mg, 25%) was reacted with 6-(5-chloro-1-(2,2, 2-trifluoroethyl)-1H-indazol-7-yl)pyrimidin-4-ol and (9R,13S)-13-amino-3-(difluoromethyl) prepared as described in Intermediate 30 -9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one It was manufactured using. MS(ESI) m/z: 647.2 (M+H) ⁺ and 649.2 (M+2+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.17 (s, 1H), 8.74 (d, J=5.1 Hz, 1H), 8.27 - 8.19 (m, 1H), 7.97 (d, J=2.0 Hz, 1H) , 7.84 - 7.72 (m, 2H), 7.68 - 7.57 (m, 2H), 7.56 - 7.51 (m, 1H), 6.77 (s, 1H), 6.14 (dd, J=12.9, 4.3 Hz, 1H), 5.51 - 5.37 (m, 2H), 2.77 - 2.70 (m, 1H), 2.45 - 2.35 (m, 1H), 2.08 (t, J=12.4 Hz, 2H), 1.64 - 1.51 (m, 2H), 1.00 (d) , J=6.8 Hz, 3H), 0.68 (br. s., 1H). Analytical HPLC (Method A): RT = 9.21 min, purity = >99%; Factor XIa Ki = 57 nM, plasma kallikrein Ki = 1,500 nM.

Example 200

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6),4,14,16-pentaen-8-one trifluoroacetate (22.1 mg, 44% yield) was purified from 6-[3-chloro-2-fluoro- 6-(1H-1,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol was reacted with 6-[5-chloro-2-(1H-1) prepared as described in Intermediate 20. ,2,3,4-tetrazol-1-yl)phenyl]pyrimidin-4-ol. MS(ESI) m/z: 593.2 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.38 (s, 1H), 8.73 - 8.65 (m, 2H), 7.84 (d, J=2.2 Hz, 1H), 7.79 - 7.42 (m, 6H), 6.46 ( s, 1H), 5.88 (dd, J=12.5, 4.2 Hz, 1H), 2.71 - 2.58 (m, 1H), 2.32 - 2.19 (m, 1H), 2.04 - 1.89 (m, 2H), 1.60 - 1.47 ( m, 1H), 1.45 - 1.30 (m, 1H), 0.94 (d, J=6.8 Hz, 3H), 0.60 (br. s., 1H). Analytical HPLC (Method A): RT = 7.93 min, purity = >99%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 10 nM.

Example 201

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6) , Preparation of 4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyri midin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6) , 4,14,16-pentaen-8-one (10.5 mg, 40% yield) was purified from (9R,13S)-13-amino-3-(difluoromethyl) in a manner similar to the procedure described in Example 200. -9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] prepared as described in Intermediate 35. It was prepared by replacing octadeca-1(18),2(6),4,14,16-pentaen-8-one. MS(ESI) m/z: 592.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.39 (s, 1H), 8.09 (s, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.78 - 7.42 (m, 7H), 7.34 (d, J=7.5 Hz, 1H), 6.51 (s, 1H), 5.76 (dd, J=12.8, 3.1 Hz, 1H), 2.51 - 2.38 (m, 1H), 2.36 - 2.21 (m, 1H), 2.11 - 1.99 (m, 1H), 1.90 - 1.77 (m, 1H), 1.58 - 1.41 (m, 2H), 1.21 - 1.03 (m, 4H) Analytical HPLC (Method A): RT = 8.50 min, purity = >99%; Factor XIa Ki = 0.1 nM, plasma kallikrein Ki = 6 nM.

Example 202

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-fluoro-6-oxo- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one

202A. Preparation of 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-fluoropyrimidin-4-ol

6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (100 mg, 0.325) in CH ₃ CN (2 mL) Selectfluor® (115 mg, 0.325 mmol) was added to the solution of (mmol). The mixture was stirred at room temperature for 1.5 hours, then DMF (0.5 ml) was added to solubilize the mixture. The reaction was heated at 85°C overnight. The reaction mixture was purified using reverse phase chromatography. After concentrating the pure fraction, the residue was partitioned between EtOAc and saturated NaHCO ₃ and the layers were separated. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over MgSO ₄ , filtered and concentrated to give 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-fluorine. Lopyrimidin-4-ol (13 mg, 12.3% yield) was obtained as an off-white foam. MS(ESI) m/z: 326.1 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.79 (s, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.66 (dd, J=8.5, 2.3 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H).

202B. (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-fluoro-6-oxo- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-fluoro-6-oxo- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2( 6),4,14,16-pentaen-8-one trifluoroacetate (3 mg, 10% yield) was reacted with 6-(5-chloro-2-(4-) in a manner similar to the procedure described in Example 56. It was prepared using chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-fluoropyrimidin-4-ol. MS(ESI) m/z: 608.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.78 - 8.68 (m, 1H), 8.41 (s, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.81 - 7.74 (m, 1H), 7.71 ( d, J=8.6 Hz, 2H), 7.52 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.00 (dd, J=12.4, 3.9 Hz, 1H), 4.05 (s, 3H) ), 2.70 (m, 1H), 2.36 - 2.23 (m, 1H), 2.14 - 1.96 (m, 2H), 1.67 - 1.54 (m, 1H), 1.53 - 1.41 (m, 1H), 1.01 (d, J =7.0 Hz, 3H), 0.68 (m., 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -77.46 (s), -147.07 (s). Analytical HPLC (Method A): RT = 9.43 min, purity = 93%; Factor XIa Ki = 0.12 nM, plasma kallikrein Ki = 13 nM.

Example 203

(9R,13S)-13-{5-bromo-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one

203A. Preparation of 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-fluoropyrimidin-4-ol

6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (100 mg, 0.325) in CH ₃ CN (2 mL) NBS (63.5 mg, 0.357 mmol) was added to the solution of (mmol). The mixture was stirred at room temperature for 1.5 hours. The reaction was partitioned between DCM and water and the layers were separated. The aqueous layer was extracted with DCM (2x). The combined organic layers were concentrated and then purified by normal phase chromatography to obtain 5-bromo-6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl. ) Pyrimidin-4-ol (117 mg, 93% yield) was obtained as a white foam. MS(ESI) m/z: 388.0 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.11 (s, 1H), 7.71 (s, 1H), 7.66 - 7.63 (m, 1H), 7.63 - 7.62 (m, 1H), 7.53 (d, J=8.4 Hz) , 1H).

203B. (9R,13S)-13-{5-bromo-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{5-bromo-4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2( 6),4,14,16-pentaen-8-one trifluoroacetate (4 mg, 13% yield) was prepared as described in Example 203A in a manner similar to the procedure described in Example 56. Prepared using parent-6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol. MS(ESI) m/z: 670.0 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.87 (s, 1H), 8.73 (d, J=5.1 Hz, 1H), 8.35 (s, 1H), 7.80 - 7.64 (m, 4H), 7.57 - 7.45 ( m, 2H), 5.99 (dd, J=12.8, 3.7 Hz, 1H), 4.05 (s, 3H), 2.72 (m, 1H), 2.40 - 2.22 (m, 1H), 2.14 - 2.00 (m, 2H) , 1.69 - 1.55 (m, 1H), 1.49 (t, J=10.0 Hz, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.69 (m, ¹ H). Analytical HPLC (Method A): RT = 11.12 min, purity = 99%; Factor XIa Ki = 4.6 nM, plasma kallikrein Ki = 220 nM.

Example 204

(9R,13S)-13-(4-{5-chloro-3-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ] Preparation of octadeca-1(18),2(6),4,14,16-pentaen-8-one

204A. Preparation of 6-(5-chloro-3-fluoro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol

6-(5-chloro-3-fluoro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol was reacted with intermediate 15 It was prepared in a similar manner, starting from 2-bromo-4-chloro-6-fluoroaniline instead of 2-bromo-4-chloroaniline. MS(ESI) m/z: 360.0 (M+H) ⁺ .

204B. (9R,13S)-13-(4-{5-chloro-3-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ] Preparation of octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{5-chloro-3-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (25 mg, 23.4%) was reacted with 6-(5) in a manner similar to Example 56. -Chloro-3-fluoro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol and as described in Intermediate 30 Prepared (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( It was prepared using 18),2(6),4,14,16-pentaen-8-one. MS(ESI) m/z: 575.1 (M+H) ⁺

¹ H NMR (400MHz, CD ₃ OD) δ 8.83 (s, 1H), 8.70 (s, 1H), 8.60 (d, J=5.3 Hz, 1H), 7.72 - 7.53 (m, 5H), 7.43 - 7.38 ( m, 1H), 6.36 (d, J=0.7 Hz, 1H), 5.89 (dd, J=12.7, 4.5 Hz, 1H), 2.60 (td, J=6.7, 3.0 Hz, 1H), 2.14 (tt, J =12.8, 4.2 Hz, 1H), 1.98 - 1.82 (m, 2H), 1.53 - 1.30 (m, 2H), 0.88 (d, J=7.0 Hz, 3H), 0.51 (br. s., 1H). Analytical HPLC (Method A): RT = 9.04 min, purity = 99.5%; Factor XIa Ki = 6.8 nM, plasma kallikrein Ki = 2,700 nM.

Example 205

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10-methyl-5,8-diazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2(7),3,5 Preparation of 15,17-hexaen-9-one

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10-methyl-5,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5 ,15,17-hexaen-9-one trifluoroacetate (0.0076 g, 36%) was prepared as described in Example 15B according to the procedure described in Example 46, 6-{5-chloro-2-[ 4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol, (10R,14S)-14-amino prepared as described in Intermediate 38 -10-methyl-5,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one, and Prepared using 4-bromopyridin-3-amine in intermediate 38B. MS(ESI) m/z: 620.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.81 (d, J=0.7 Hz, 1H), 8.77 (s, 2H), 8.29 (s, 1H), 8.08 (d, J=5.7 Hz, 1H), 7.91 - 7.84 (m, 2H), 7.82 - 7.60 (m, 4H), 7.42 - 7.34 (m, 1H), 6.49 (d, J=0.4 Hz, 1H), 5.80 (dd, J=13.0, 3.5 Hz, 1H) ), 2.64 - 2.51 (m, 1H), 2.39 - 2.26 (m, 1H), 2.18 - 2.06 (m, 1H), 1.99 - 1.88 (m, 1H), 1.63 - 1.30 (m, 3H), 1.16 (d) , J=6.8 Hz, 3H). Analytical HPLC (Method A): RT = 6.87 min, purity = 90%; Factor XIa Ki = 0.11 nM, plasma kallikrein Ki = 11 nM.

Example 206

(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-10-methyl-5,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15,17- Preparation of hexaen-9-one

(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-10-methyl-5,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15,17- Hexaen-9-one trifluoroacetate (0.0062 g, 31%) was added to 6-[5-chloro-2-(4-chloro-1H-) prepared as described in Intermediate 9E according to the procedure described in Example 205. 1,2,3-triazol-1-yl)phenyl] was prepared using pyrimidin-4-ol. MS(ESI) m/z: 586.1 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.70 (d, J=5.3 Hz, 1H), 8.64 (s, 1H), 8.37 - 8.28 (m, 2H), 7.93 - 7.84 (m, 3H), 7.75 ( dd, J=8.6, 2.2 Hz, 1H), 7.68 - 7.61 (m, 3H), 7.43 - 7.35 (m, 1H), 6.42 (s, 1H), 5.82 (dd, J=13.0, 3.5 Hz, 1H) , 2.63 - 2.52 (m, 1H), 2.41 - 2.28 (m, 1H), 2.20 - 2.08 (m, 1H), 1.98 - 1.87 (m, 1H), 1.65 - 1.45 (m, 2H), 1.41 - 1.29 ( m, 1H), 1.17 (d, J=7.0 Hz, 3H). Analytical HPLC (Method A): RT = 6.26 min, purity = 90%; Factor XIa Ki = 0.2 nM, plasma kallikrein Ki = 17 nM.

Example 207

(9R,13S)-13-[4-(6-chloro-1H-1,3-benzodiazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3 -(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16 -Preparation of pentaen-8-one

207A. Preparation of 6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole.

4-Bromo-6-chloro-1H-benzo[d]imidazole (0.600 g, 2.59 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2, 2'-Bi(1,3,2-dioxaborolane) (0.790 g, 3.11 mmol) and KOAc (0.763 g, 7.78 mmol) were added to dioxane (10.9 mL). After bubbling Ar through the solution for 2 minutes, Pd(dppf)Cl ₂ CH ₂ Cl ₂ complex (0.106 g, 0.130 mmol) was added and the mixture was heated at 110° C. overnight. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The organic phase was separated, washed with saturated NaHCO ₃ and brine, dried over MgSO ₄ , filtered and concentrated to give a crude dark solid product which was carried over to the subsequent reaction. MS(ESI) m/z: 197.0 (MC ₆ H ₁₀ +H) ⁺ .

207B. Preparation of 6-chloro-4-(6-methoxypyrimidin-4-yl)-1H-benzo[d]imidazole

4-Chloro-6-methoxypyrimidine (0.562 g, 3.89 mmol), 6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxa) in DME (20.74 mL) Borolan-2-yl)-1H-benzo[d]imidazole (0.722 g, 2.59 mmol) and 2 M aqueous Na ₂ CO ₃ (0.549 g, 5.18 mmol), EtOH (2.59 mL) purged with Ar for minutes. did. Then PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.212 g, 0.259 mmol) was added and heated to 90°C. After 2 hours, the reaction was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a brown oil. The crude material was purified by normal phase chromatography using EtOAc and MeOH as eluents to give 6-chloro-4-(6-methoxypyrimidin-4-yl)-1H-benzo[d]imidazole (148 mg, 22 %) was obtained. MS(ESI) m/z: 261.1 (M+H) ⁺ and 263.1 (M+2+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 8.93 (d, J=1.1 Hz, 1H), 8.42 (s, 1H), 8.36 (br. s., 1H), 8.20 (d, J=1.9 Hz, 1H), 7.84 (s, 1H), 4.02 (s, 3H).

207C. Preparation of 6-(6-chloro-1H-benzo[d]imidazol-4-yl)pyrimidin-4-ol

To a clear solution of 6-chloro-4-(6-methoxypyrimidin-4-yl)-1H-benzo[d]imidazole (0.148 g, 0.568 mmol) in AcOH (2.88 ml) was added 63% aqueous HBr (0.548 ml, 4.54 mmol) was added and the reaction mixture was heated to 80°C. After 1 hour, the solution was cooled to room temperature, diluted with EtOAc (10 ml) and then quenched with saturated aqueous NaHCO ₃ (20 ml). The aqueous layer was extracted with EtOAc (3x 10 ml). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was triturated with petroleum ether, filtered and dried under vacuum to give 6-(6-chloro-1H-benzo[d]imidazol-4-yl)pyrimidin-4-ol as a beige solid. . MS(ESI) m/z: 247 (M+H) ⁺ and 249 (M+2+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.39 (s, 1H), 8.35 - 8.28 (m, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.78 (d, J=2.2 Hz, 2H ).

207D. (9R,13S)-13-[4-(6-chloro-1H-1,3-benzodiazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3 -(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16 -Preparation of pentaen-8-one trifluoroacetate

(9R,13S)-13-[4-(6-chloro-1H-1,3-benzodiazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3 -(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16 -Pentaen-8-one trifluoroacetate (0.7 mg, 0.77%) was reacted with 6-(6-chloro-1H-benzo[d]imidazol-4-yl)pyrimidine-4 in a manner similar to Example 56. -ol and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0] prepared as described in Intermediate 30 ^2,6 ]Octadeca-1(18),2(6),4,14,16-pentaen-8-one was used to prepare it. MS(ESI) m/z: 565 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.43 (s, 1H), 9.07 (br. s., 1H), 8.76 (d, J=4.6 Hz, 1H), 8.43 (br. s., 1H) , 8.10 (d, J=17.7 Hz, 1H), 7.99 - 7.90 (m, 2H), 7.82 - 7.73 (m, 2H), 7.44 (d, J=4.6 Hz, 1H), 5.99 (d, J=11.0) Hz, 1H), 2.09 (d, J=8.9 Hz, 1H), 1.98 (br. s., 1H), 1.55 (br. s., 4H), 1.40 (br. s., 1H), 0.90 (d , J=6.7 Hz, 3H). Analytical HPLC (Method C): RT = 1.20 min, purity = 100%; Factor XIa Ki = 120 nM.

Example 208

Methyl 4-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl) phenyl]-6-oxo-1 ,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2 , 5,14,16-pentaen-4-yl] Preparation of piperidine-1-carboxylate

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]- prepared as described in Example 328 6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(piperidin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2,5,14,16-pentaen-8-one (0.015 g, 0.023 mmol), methyl chloroformate (2.2 mg, 0.023 mmol), and Et ₃ N (0.016 mL, 0.114 mmol) was dissolved in THF (1 mL), stirred at room temperature for 3 hours and then concentrated. The residue was purified by reverse phase chromatography to obtain methyl 4-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazole-1- I) phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-4-yl]piperidine-1-carboxylate (10 mg, 61%) was obtained as a white solid. MS(ESI) m/z: 717.2 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.69 - 8.64 (m, 1H), 8.63 - 8.57 (m, 1H), 8.36 (s, 1H), 7.91 (d, J=2.4 Hz, 2H), 7.83 ( s, 1H), 7.79 - 7.72 (m, 1H), 7.68 (s, 1H), 7.67 - 7.65 (m, 1H), 7.65 - 7.61 (m, 1H), 6.40 (d, J=0.4 Hz, 1H) , 6.11 - 5.99 (m, 1H), 4.52 - 4.41 (m, 1H), 4.34 - 4.22 (m, 2H), 3.74 (s, 3H), 3.17 - 2.97 (m, 2H), 2.86 - 2.75 (m, 1H), 2.36 - 2.13 (m, 4H), 2.13 - 1.97 (m, 3H), 1.81 - 1.63 (m, 1H), 1.61 - 1.48 (m, 1H), 1.09 (d, J=7.0 Hz, 3H) . Analytical HPLC (Method A): RT = 7.40 min, purity = 99%; Factor XIa Ki = 7 nM, plasma kallikrein Ki = 460 nM.

Example 209

(9R,13S)-13-(4-{4-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{4-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca- 1(18),2(6),4,14,16-pentaen-8-one (4 mg, 20% yield) was purified from 6-{ using the HATU, DBU coupling methodology as described in Example 56. 4-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (0.01 g, 0.028 mmol) and (9R, 13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), prepared as a solid through coupling of 4,14,16-pentaen-8-one (0.01 g, 0.028 mmol). LCMS m/z = 660.2 (M+H).

^1H NMR (400MHz, CD ₃ OD) δ 8.87 - 8.80 (m, 2H), 8.76 - 8.71 (m, 1H), 7.86 - 7.83 (m, 2H), 7.82 - 7.80 (m, 1H), 7.77 - 7.76 (m, 1H), 7.72 - 7.66 (m, 2H), 7.55 - 7.52 (m, 1H), 6.49 - 6.46 (s, 1H), 6.08 - 5.99 (m, 1H), 2.78 - 2.68 (m, 1H) , 2.36 - 2.21 (m, 1H), 2.12 - 1.99 (m, 3H), 1.69 - 1.41 (m, 4H), 1.05 - 0.96 (d, 3H), 0.74 - 0.54 (m, 1H). Analytical HPLC (Method A) RT = 8.77 min, purity = 95%; Factor XIa Ki = 48 nM.

Example 210

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo-1 ,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), Preparation of 4,14,16-pentaen-8-one

210A. Preparation of 4-chloro-2-(6-methoxy-5-methylpyrimidin-4-yl)aniline

4-Chloro-2-(6-methoxy-5-methylpyrimidin-4-yl)aniline (230 mg, 73% yield) was purified from 4-chloro-6-methoxypyrimidine in a manner similar to the procedure described for Intermediate 9B. It was prepared by replacing 4-chloro-6-methoxy-5-methylpyrimidine (200 mg, 1.261 mmol). MS(ESI) m/z: 250.1 (M+H) ⁺ .

^1H NMR (500MHz, CDCl ₃ ) δ 8.68 (s, 1H), 7.15 (dd, J=8.6, 2.6 Hz, 1H), 7.09 (d, J=2.6 Hz, 1H), 6.72 (d, J=8.6) Hz, 1H), 4.25 (br. s., 2H), 4.06 (s, 3H), 2.14 (s, 3H), 1.33 - 1.20 (m, 12H).

210B. Preparation of 4-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-5-methylpyrimidine

4-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-5-methylpyrimidine (70 mg, 20 % yield) was obtained by reacting 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline to 4-chloro-2-(6-methoxy-5-methylpyrimidine) in a manner similar to the procedure described for Intermediate 9C. -4-yl) was prepared by replacing it with aniline (230 mg, 0.921 mmol). MS(ESI) m/z: 374.4 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.36 (s, 1H), 7.44 - 7.29 (m, 2H), 7.25 (d, J=2.2 Hz, 1H), 7.12 (s, 1H), 3.76 - 3.70 (m , 3H), 0.04-0.05 (m, 9H).

210C. Preparation of 4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-5-methylpyrimidine

4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-5-methylpyrimidine (29 mg, 46% yield) 4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimi in a manner similar to the procedure described in intermediate 9D. Dean 4-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-5-methylpyrimidine (70 mg , 0.187 mmol). MS(ESI) m/z: 336.4 (M+H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.60 (s, 1H), 7.61 - 7.58 (m, 2H), 7.50 (s, 1H), 7.47 (d, J=2.0 Hz, 1H), 4.02 (s, 3H) ), 1.83 (s, 3H).

210D. Preparation of 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-ol

6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-ol (10 mg, 36% yield) 4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine was reacted with 4-methoxypyrimidine in a manner similar to the procedure described in Intermediate 9E. (5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-5-methylpyrimidine (29 mg, 0.086 mmol) Manufactured. MS(ESI) m/z: 322.0 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.25 (s, 1H), 7.98 (s, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.71 (d, J=0.4 Hz, 1H), 7.66 (dd, J=2.1, 0.6 Hz, 1H), 1.79 (s, 3H).

210E. (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo-1 ,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), 4,14,16-pentaen-8-one trifluoroacetate production

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo-1 ,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6) ),4,14,16-pentaen-8-one trifluoroacetate (8.8 mg, 37% yield) was purified from 6-(5-chloro-2-(4-chloro) in a manner similar to the procedure described in Example 56. It was prepared using -1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-ol (0.010 g, 0.031 mmol). MS(ESI) m/z: 604.1 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.79 - 8.70 (m, 2H), 8.27 (s, 1H), 7.78 (s, 1H), 7.77 - 7.69 (m, 2H), 7.68 (d, J=2.0 Hz, 1H), 7.60 (dd, J=5.3, 1.5 Hz, 1H), 7.50 (s, 1H), 5.95 (dd, J=12.5, 4.2 Hz, 1H), 4.06 (s, 3H), 2.70 (m , 1H), 2.40 - 2.29 (m, 1H), 2.13 - 1.99 (m, 2H), 1.77 (s, 3H), 1.67 - 1.55 (m, 1H), 1.47 (m, 1H), 1.02 (d, J =6.8 Hz, 3H), 0.77 (m., 1H); Analytical HPLC (Method A): RT = 7.79 min, purity = 93%; Factor XIa Ki = 3.5 nM, plasma kallikrein Ki = 240 nM.

Example 211

(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4 Preparation of 7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

211A. Preparation of 4-(5-chloro-2-iodophenyl)-6-methoxypyrimidine

A solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (2 g, 8.49 mmol) prepared as described in Intermediate 8A in ACN (56.6 ml) was cooled to 0° C. p-TsOH·H ₂ O (4.04 g, 21.22 mmol) was added. A solution of NaNO ₂ (1.171 g, 16.97 mmol) and NaI (3.18 g, 21.22 mmol) in water (28.3 ml) was added slowly and the reaction turned into a dark brown solution. After a few minutes, the reaction turned cloudy. The reaction was stirred at 0° C. for 1 hour and then allowed to warm to room temperature. After 18 hours, the reaction was quenched with saturated NaHCO ₃ and extracted with EtOAc. The organic layer was washed with saturated aqueous Na ₂ S ₂ O ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a solid. Purification by normal phase chromatography gave 4-(5-chloro-2-iodophenyl)-6-methoxypyrimidine (2.13 g, 72% yield) as a white solid. MS(ESI) m/z: 347.2 (M+H) ⁺ .

^1H NMR (500MHz, CDCl ₃ ) d 8.87 (d, J=1.1 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.44 (d, J=2.8 Hz, 1H), 7.11 (dd, J=8.5, 2.8 Hz, 1H), 6.93 (d, J=1.4 Hz, 1H), 4.06 (s, 3H).

211B. Preparation of 6-(5-chloro-2-iodophenyl)pyrimidin-4-ol

6-(5-chloro-2-iodophenyl)pyrimidin-4-ol (0.24 g, 100% yield) was reacted with 4-(5-chloro-2-(1-) in a manner similar to the procedure described in Example 140B. (difluoromethyl)-1H-pyrazol-4-yl)phenyl)-6-methoxypyrimidine was added to 4-(5-chloro-2-iodophenyl)-6-methoxypyrimidine (0.25 g, 0.721 mmol), and the reaction time was 1 hour at 85°C. MS(ESI) m/z: 333.0 (M+H) ⁺ .

^1H NMR (400MHz, CD ₃ OD) δ 8.27 (d, J=0.9 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.47 (d, J=2.6 Hz, 1H), 7.21 (dd , J=8.6, 2.6 Hz, 1H), 6.54 (d, J=0.9 Hz, 1H).

211C. (9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4 ,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate production

(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4 ,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (125 mg, 68% yield) was prepared using 6-(5-chloro-2-iodophenyl)pyrimidin-4-ol (100 mg, 0.301 mmol) in a manner similar to the procedure described in Example 56. MS(ESI) m/z: 615.4 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.05 (s, 1H), 8.75 (d, J=5.3 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.54 (dd, J=5.1, 1.5 Hz, 1H), 7.51 - 7.49 (m, 2H), 7.21 (dd, J=8.5, 2.5 Hz, 1H), 6.60 (s, 1H), 6.07 (dd, J=12.8 , 4.4 Hz, 1H), 4.05 (s, 3H), 2.77 - 2.68 (m, 1H), 2.38 (tt, J=12.7, 4.3 Hz, 1H), 2.16 - 2.02 (m, 2H), 1.68 - 1.44 ( m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.79 - 0.64 (m, 1H). Analytical HPLC (Method A): RT = 8.71 min, 99.6% purity; Factor XIa Ki = 12 nM, plasma kallikrein Ki = 140 nM.

Example 212

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2( 6),4,14,16-pentaen-8-one (3 mg, 19% yield) was prepared as described in Intermediate 9 in a manner similar to the procedure described in Example 56. -Fluoro-6-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol (9 mg, 0.024 mmol), and (9R,13S)-13 -Amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene Prepared using -8-one (7.3 mg, 0.024 mmol). LCMS m/z 650.3 (M+H).

^1H NMR (400MHz, CD ₃ OD) δ 8.81 - 8.77 (m, 1H), 8.62 - 8.57 (m, 1H), 8.56 - 8.54 (m, 1H), 7.93 - 7.87 (m, 1H), 7.84 - 7.78 (m, 3H), 7.66 - 7.62 (dd, 1H), 7.61 - 7.57 (m, 1H), 7.52 (bs, 1H), 7.49 - 7.44 (m, 2H), 7.43 - 7.38 (m, 1H), 6.68 - 6.64 (m, 1H), 5.98-5.94(m, 1H), 4.07 (s, 3H), 2.75 - 2.61 (m, 1H), 2.39 - 2.22 (m, 1H), 2.10 - 1.99 (m, 2H) , 1.65 - 1.53 (m, 1H), 1.49 - 1.33 (m, 1H), 1.07 - 1.00 (d, 3H), 0.86 - 0.67 (m, 1H); Factor XIa Ki = 0.81 nM, plasma kallikrein Ki = 28 nM.

Example 213

N-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl) Preparation of carbamate trifluoroacetate

213A. Preparation of N-[4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl]carbamate

4-Chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (0.024 g, 0.095 mmol) was dissolved in DCM (5 ml). To this solution was sequentially added TEA (1 mL) followed by methyl chloroformate (8.94 mg, 0.095 mmol), and the solution was stirred at room temperature. After 2 hours, the reaction was concentrated in vacuo to an oil and quenched with dilute HCl (5 mL). The organic portion was extracted with EtOAc (2x25 mL), dried over MgSO ₄ and evaporated to give an oil. LCMS m/z 312.1 (M+H).

^1H NMR (400MHz, CDCl ₃ ) δ 10.30 - 10.24 (m, 1H), 8.84 - 8.81 (m, 1H), 8.00 - 7.92 (m, 1H), 7.40 - 7.32 (m, 1H), 7.05 - 7.01 ( m, 1H), 3.98 (s, 3H), 3.67 (s, 3H). The crude product was taken into a small vial, dissolved in AcOH (1 mL), 48% HBr (0.1 mL) was added and heated at 80° C. until the reaction was complete. The reaction mixture was concentrated, quenched with water (25 mL) and extracted with EtOAc (2x25 mL). The combined organic layers were dried and evaporated to give N-[4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)phenyl]carbamate as a white film (13 mg). . LCMS m/z 299.1 (M+H).

213B. N-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl) Preparation of Carbamates

N-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl) Carbamate (1.1 mg, 4.21% yield) was purified from N-[4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl]carbamate following the procedure described in Example 56. Mate (13 mg, 0.044 mmol), (9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( It was prepared using 18),2(6),4,14,16-pentaen-8-one (15 mg, 0.044 mmol). LCMS m/z 580.1 (M+H).

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.39 - 9.34 (m, 1H), 9.24 - 9.21 (m, 1H), 9.05 - 9.02 (m, 1H), 8.74 - 8.70 (m, 1H), 7.74 - 7.57 (m, 3H), 7.49 (s, 1H), 6.61 - 6.55 (m, 1H), 5.99 - 5.87 (m, 1H), 4.04 - 3.98 (m, 3H), 3.65 - 3.59 (m, 3H), 2.70 - 2.62 (m, 1H), 2.40 - 2.32 (m, 1H), 2.18 - 2.09 (m, 1H), 1.96 - 1.85 (m, 1H), 1.53 - 1.30 (m, 2H), 0.94 - 0.87 (m , 3H), 0.56 - 0.36 (m, 1H). Orto RT. 1.605 minutes purity 97%; Factor XIa Ki = 110 nM.

Example 214

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 Preparation of (18),2(6),4,14,16-pentaen-15-ium-15-oleate

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]- prepared as described in Example 88 6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]Octadeca-1(18),2(6),4,14,16-pentaen-8-one was dissolved in EtOAc (2 mL) and m-CPBA (0.021 g, 0.120 mmol) was added at room temperature. did. After stirring overnight, the reaction was concentrated and purified by reverse phase chromatography to obtain (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazole -1-yl) phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15 -Tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-15-ium-15-oleate (11 mg, 15%) was obtained as a white solid. MS(ESI) m/z: 642.2 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.54 (s, 1H), 8.71 (s, 1H), 8.40 (d, J=6.7 Hz, 2H), 7.98 - 7.86 (m, 3H), 7.85 - 7.76 (m, 2H), 7.72 (d, J=8.5 Hz, 1H), 7.55 (d, J=5.2 Hz, 1H), 6.32 (s, 1H), 5.49 - 5.31 (m, 1H), 2.48 - 2.34 ( m, 1H), 2.03 - 1.92 (m, 1H), 1.82 - 1.70 (m, 1H), 1.48 - 1.36 (m, 1H), 1.06 (d, J=6.1 Hz, 3H), 1.01 - 0.85 (m, 1H). Analytical HPLC (Method C): RT = 1.45 min, purity = 100%; Factor XIa Ki = 0.35 nM, plasma kallikrein Ki = 74 nM.

Example 215

(9R,13S)-13-(4-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo -1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 Preparation of (18),2(6),4,14,16-pentaen-8-one trifluoroacetate

215A. Preparation of 6-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]phenyl} pyrimidin-4-ol

4-Chloro-2-(6-methoxypyrimidin-4-yl)aniline (0.1 g, 0.424 mmol) was dissolved in ACN (5 mL) and cooled to 0°C. Isopentylnitrite (0.075 g, 0.636 mmol) was added to this solution, followed by TMSN ₃ (0.073 g, 0.636 mmol). The reaction mixture was stirred at 0° C. for 0.5 hours and then allowed to warm to room temperature and stirred overnight. Cu ₂ O (6.1 mg, 0.042 mmol) followed by 3-ethynylpyridine (0.044 g, 0.424 mmol) was added to the solution and stirred at room temperature. The reaction changed from milky gray to transparent within about 2 minutes. After 1 hour, the reaction was concentrated and purified directly by 12 g silica gel ISCO column using hexane/EtOAc as eluent to give 6-{5-chloro-2-[4-(pyridin-3-yl)-1H. -1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (0.069 g) was obtained as a yellowish-orange liquid. LCMS m/z 355.1 (M+H).

^1H NMR (500MHz, CDCl ₃ ) δ 8.89 - 8.86 (m, 1H), 7.91 - 7.88 (m, 1H), 7.49 - 7.45 (m, 1H), 7.29 (s, 5H), 7.27 - 7.20 (m, 2H), 4.10 - 4.04 (m, 3H). The product was dissolved in AcOH (1 mL), 48% aqueous HBr (0.2 mL) was added, sealed and heated at 80° C. for 2 hours. The reaction was concentrated, quenched with saturated NaHCO ₃ (25 mL) and extracted with EtOAc (2x25 mL). The organic extracts were combined, dried over MgSO ₄ , filtered and concentrated to give 6-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl. ]Phenyl}pyrimidin-4-ol was obtained as an oil (0.011 g, 7% yield). LCMS m/z 351.1 (M+H).

215B. (9R,13S)-13-(4-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo -1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 Preparation of (18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{5-chloro-2-[4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo -1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octadeca-1 (18),2(6),4,14,16-pentaen-8-one trifluoroacetate was reacted with 6-{5-chloro-2-[4-(pyridine-3) according to the procedure described in Example 56. -yl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (12 mg, 0.034 mmol) and (9R,13S)-13-amino-3-(difluoro Romethyl)-9-methyl-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaene-8- It was prepared using (11 mg, 0.034 mmol) (3.5 mg, 14.1%). LCMS m/z 668.1 (M+H).

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.45 - 9.41 (m, 1H), 9.13 - 9.09 (m, 1H), 9.02 - 8.97 (m, 1H), 8.69 - 8.62 (m, 1H), 8.53 - 8.47 (m, 1H), 8.35 - 8.29 (m, 1H), 7.99 - 7.95 (m, 2H), 7.93 - 7.83 (m, 4H), 7.75 - 7.70 (m, 1H), 7.64 - 7.59 (m, 1H) ), 7.55 - 7.50 (m, 1H), 7.49 - 7.42 (m, 1H), 7.41 - 7.32 (m, 1H), 7.29 - 7.23 (m, 1H), 6.50 - 6.46 (m, 1H), 5.71 - 5.59 (m, 1H), 2.55 - 2.29 (m, 2H), 1.99 - 1.81 (m, 2H), 1.54 - 1.39 (m, 1H), 1.28 - 1.06 (m, 2H), 1.05 - 0.98 (d, 3H) , 0.50 - 0.31 (m, 1H). Orthogonal RT. 1.652 Purity >92%; Factor XIa Ki = 0.48 nM, plasma kallikrein Ki = 75 nM.

Example 216

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-4-(pyridin-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of 2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]- prepared as described in Example 101 6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18), 2(6),4,14,16-pentaen-8-one (0.09 g, 0.156 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.022 g, 0.156 mmol) ), Cs ₂ CO ₃ (0.102 g, 0.312 mmol), and 3-iodopyridine (0.032 g, 0.156 mmol) were added to a 5 mL microwave vial. DMF (2 mL) was added and the vial was purged with Ar (3x). CuI (2 mg, 10.50 μmol) was added, the vial was sealed with a microwave vial stopper, and the reaction was heated at 120° C. for 30 min in a microwave reactor. The reaction was then purified by reverse phase chromatography to obtain (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl ]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one trifluoroacetate (52 mg, 42% yield) was obtained as a tan solid. MS(ESI) m/z: 653.6 (M+H) ⁺ .

^1H NMR (400MHz, CD ₃ OD) δ 9.34 - 9.21 (m, 1H), 8.81 - 8.73 (m, 1H), 8.72 - 8.64 (m, 2H), 8.60 (s, 2H), 8.37 (s, 1H) ), 8.02 - 7.96 (m, 1H), 7.96 - 7.89 (m, 1H), 7.87 - 7.80 (m, 1H), 7.80 - 7.73 (m, 2H), 7.72 - 7.63 (m, 1H), 6.47 - 6.35 (m, 1H), 6.20 - 6.03 (m, 1H), 2.96 - 2.82 (m, 1H), 2.42 - 2.22 (m, 2H), 2.17 - 2.01 (m, 1H), 1.83 - 1.70 (m, 1H) , 1.70 - 1.52 (m, 1H), 1.42 - 1.26 (m, 1H), 1.11 (d, J=7.0 Hz, 3H), 0.97 - 0.85 (m, 2H). Analytical HPLC (Method A): RT = 6.69 min, purity = 97.5%; Factor XIa Ki = 0.57 nM, plasma kallikrein Ki = 10 nM.

Example 217

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-3-(pyridin-3-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of ,2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-methyl-3-(pyridin-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18) ,2(6),4,14,16-pentaen-8-one trifluoroacetate (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1, 2,3-triazol-1-yl) phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-3-yl)-3,4, A side product from the reaction to produce 7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one, Example 216 ( 24 mg, 19% yield). MS(ESI) m/z: 653.6 (M+H) ⁺ .

^1H NMR (400MHz, CD ₃ OD) δ 9.27 - 9.27 (m, 1H), 9.30 - 9.21 (m, 1H), 8.63 (s, 6H), 8.39 (s, 1H), 8.17 - 8.09 (m, 1H) ), 7.95 - 7.90 (m, 1H), 7.88 - 7.83 (m, 1H), 7.82 - 7.73 (m, 3H), 7.71 - 7.65 (m, 1H), 6.50 - 6.37 (m, 1H), 5.95 - 5.80 (m, 1H), 2.78 - 2.60 (m, 1H), 2.55 - 2.39 (m, 1H), 2.15 - 1.98 (m, 2H), 1.83 - 1.65 (m, 1H), 1.61 - 1.44 (m, 2H) , 1.32 (d, J=7.0 Hz, 5H). Analytical HPLC (Method A): RT = 6.45 min, purity = 95%; Factor XIa Ki = 74 nM, plasma kallikrein Ki = 600 nM.

Example 218

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6), Preparation of 4,14,16-pentaen-8-one

218A. Preparation of 4-nitro-1-phenyl-1H-pyrazole

4-nitro-1H-pyrazole (3.0 g, 26.5 mmol), phenylboronic acid (5.18 g, 42.4 mmol), NaOH (1.061 g, 26.5 mmol), CuCl ₂ (0.357 g, 2.65 mmol) and MeOH (25 mL) was added. The reaction mixture was then refluxed overnight with air bubbled through it. The solvent was then removed under vacuum and the crude product was purified by silica gel chromatography to give 4-nitro-1-phenyl-1H-pyrazole (3.5 g, 17.58 mmol, 66% yield) as a white solid. MS(ESI) m/z: 190.1 [M+H] ⁺ .

218B. (S)-tert-Butyl (1-(4-(4-nitro-1-phenyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate manufacture of

( _S )-tert-butyl (1-(4-chloropyridin-2-yl) but-3-en-1-yl)carbamate prepared as described in Intermediate 23 in 500 mL RBF, flushed with N 2 (2.5 g, 8.84 mmol), 4-nitro-1-phenyl-1H-pyrazole (1.67 g, 8.84 mmol) and dioxane (50 mL) were added. The solution was bubbled with N ₂ for 5 min, Pd(OAc) ₂ (0.1 g, 0.442 mmol), di(adamantan-1-yl)(butyl)phosphine (0.317 g, 0.884 mmol), K ₂ CO ₃ (3.67 g, 26.5 mmol) and PvOH (0.271 g, 0.265 mmol) were added. The reaction mixture was bubbled with N ₂ for 5 minutes and then heated to 100° C. for 3 hours. Water (200 mL) was added. The reaction mixture was extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried over Na ₂ SO ₄ , filtered and concentrated. Purified by normal phase chromatography eluting with gradient hexane/EtOAc to give (S)-tert-butyl (1-(4-(4-nitro-1-phenyl-1H-pyrazol-5-yl)pyridin-2-yl. )But-3-en-1-yl)carbamate (3.0 g, 6.54 mmol, 74% yield) was obtained as a pale yellow oil. MS(ESI) m/z: 436.5 [M+H] ⁺ .

218C. (9R,13S)-13-amino-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) , Preparation of 4,14,16-pentaen-8-one

(9R,13S)-13-amino-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6) , 4,14,16-pentaen-8-one was reacted with (S)-tert-butyl (1-(4-(4-nitro-1-phenyl-1H-pyrazole-5) in a manner similar to that described in Intermediate 30. It was prepared using -yl)pyridin-2-yl)but-3-en-1-yl)carbamate (0.11 g, 0.34 mmol, 90% yield). MS(ESI) m/z: 362.5 [M+H] ⁺ .

218D. (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,14,16-pentaen-8-one trifluoroacetate (0.024 g, 0.030 mmol, 33% yield) was prepared as described in Intermediate 9 in a manner similar to the procedure described in Example 56. -Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (0.028 g, 0.091 mmol), and (9R,13S)-13- Amino-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-penta Prepared using en-8-one (0.033 g, 0.091 mmol).

¹ H NMR (400MHz, CD ₃ OD) δ 8.81 (s, 1H), 8.39 (d, J=5.3 Hz, 1H), 8.32 (s, 1H), 7.87 (d, J=2.4 Hz, 2H), 7.76 - 7.68 (m, 2H), 7.65 - 7.60 (m, 1H), 7.51 - 7.38 (m, 5H), 6.66 (dd, J=5.1, 1.5 Hz, 1H), 6.37 (s, 1H), 6.02 (dd , J=12.7, 4.3 Hz, 1H), 3.34 (s, 1H), 2.76 (td, J=6.5, 3.1 Hz, 1H), 2.36 - 2.23 (m, 1H), 2.18 - 2.08 (m, 1H), 2.06 - 1.91 (m, 1H), 1.74 - 1.56 (m, 1H), 1.55 - 1.39 (m, 1H), 1.02 (d, J=7.0 Hz, 3H), 0.65 (br. s., 1H). MS(ESI) m/z: 652.6 [M+H] ⁺ . Analytical HPLC (Method A): RT = 9.41 min, purity = >95.0%; Factor XIa Ki = 83 nM, plasma kallikrein Ki = 2,700 nM.

Example 219

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin-3-yl}- 6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]Preparation of octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin-3-yl as a solid }-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (4 mg, 3% yield) was subjected to the HATU, DBU coupling methodology as described in Example 56. Using 6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin-3-yl}pyrimidin-4-ol ( 0.014 g, 0.04 mmol) and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] It was prepared through coupling of octadeca-1(18),2(6), 4,14,16-pentaen-8-one (0.014 g, 0.04 mmol). MS m/z = 661.2 (M+H) ⁺ .

^1H NMR (400MHz, CD ₃ OD) δ 9.30 - 9.27 (m, 1H), 9.08 - 9.03 (m, 1H), 8.79 (s, 2H), 8.37 - 8.33 (m, 1H), 7.78 - 7.74 (m , 2H), 7.70 - 7.67 (m, 1H), 7.59 - 7.51 (m, 1H), 6.14 - 6.00 (m, 1H), 2.81 - 2.68 (m, 1H), 2.47 - 2.29 (m, 1H), 2.16 - 2.01 (m, 2H), 1.70 - 1.46 (m, 2H), 1.07 - 0.96 (d, 3H), 0.75 - 0.55 (m, 1.H). Analytical HPLC (Method A) RT = 11.3 min, purity = 98%; Factor XIa Ki = 35 nM, plasma kallikrein Ki = 7,200 nM.

Example 220

(9R,13S)-13-(5-bromo-4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin- 3-yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3 Preparation of .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(5-bromo-4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin- 3-yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one was reacted with 5- using the HATU, DBU coupling methodology as described in Example 56. Bromo-6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin-3-yl}pyrimidin-4-ol Containing 6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pyridin-3-yl}pyrimidin-4-ol (0.014 g, 0.04 mmol) and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa The by-product of Example 219 (3 mg, 9% yield) as a solid via coupling with deca-1(18),2(6), 4,14,16-pentaen-8-one (0.014 g, 0.04 mmol) ) was isolated as. MS m/z = 740.4(M+H) ⁺ . Analytical HPLC (Method A) RT = 12.2 min, purity = 93%; Factor XIa Ki = 250 nM, plasma kallikrein Ki = 7,000 nM.

Example 221

(9R,13S)-13-(4-{5-chloro-4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl} -6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ] Preparation of octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl] as a solid Phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (4 mg, 15% yield) using the HATU, DBU coupling methodology as described above. 6-{5-chloro-4-fluoro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (0.013 g, 0.036 mmol) and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa It was prepared through coupling of deca-1(18),2(6), 4,14,16-pentaen-8-one (0.012 g, 0.036 mmol). MS m/z = 678.1 (M+H).

^1H NMR (400MHz, CD ₃ OD) δ 8.88 - 8.82 (m, 2H), 8.75 - 8.72 (m, 1H), 8.10 - 8.04 (m, 1H), 7.76 (s, 2H), 7.72 - 7.65 (m , 1H), 7.56 - 7.51 (m, 1H), 6.46 (s, 1H), 6.09 - 5.96 (m, 1H), 4.07 - 3.99 (m, 1H), 3.53 - 3.44 (m, 1H), 2.81 - 2.64 (m, 1H), 2.37 - 2.21 (m, 1H), 2.09 - 1.96 (m, 2H), 1.68 - 1.42 (m, 2H), 1.02 (d, J=7.0 Hz, 3H); Factor XIa Ki = 4.7 nM, plasma kallikrein Ki = 1,300 nM.

Example 222

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18), Preparation of 2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1 (18), 2(6),4,14,16-pentaen-8-one trifluoroacetate (4.5 mg, 0.005 mmol, 6% yield) was prepared as described in Intermediate 15 in a manner similar to the procedure described in Example 56. 6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (0.031 g, 0.091 mmol) , and (9R,13S)-13-amino-9-methyl-3-phenyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] prepared as described in Example 218 C. It was prepared using octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.033 g, 0.091 mmol).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.80 (d, J=0.9 Hz, 1H), 8.77 (s, 1H), 8.37 (d, J=5.3 Hz, 1H), 7.89 (d, J=2.2 Hz) , 1H), 7.86 (s, 1H), 7.78 - 7.72 (m, 2H), 7.71 - 7.66 (m, 1H), 7.50 - 7.39 (m, 5H), 6.66 (dd, J=5.1, 1.5 Hz, 1H ), 6.45 (d, J=0.7 Hz, 1H), 6.03 (dd, J=12.7, 4.3 Hz, 1H), 3.35 (s, 1H), 2.76 (td, J=6.6, 3.1 Hz, 1H), 2.27 (tt, J=12.7, 4.5 Hz, 1H), 2.18 - 2.06 (m, 1H), 2.05 - 1.92 (m, 1H), 1.70 - 1.55 (m, 1H), 1.54 - 1.41 (m, 1H), 1.03 (d, J=6.8 Hz, 3H), 0.66 (br. s., 1H). MS(ESI) m/z: 686.6 [M+H] ⁺ . Analytical HPLC (Method A): RT = 10.03 min, purity = >95.0%; Factor XIa Ki = 48 nM, plasma kallikrein Ki = 3,700 nM.

Example 223

(9R,13S)-13-(4-{4,5-dichloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6- Oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{4,5-dichloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}- as a solid 6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]Octadeca-1(18),2(6),4,14,16-pentaen-8-one (5 mg, 22% yield) was prepared using the HATU, DBU coupling methodology as described in Example 56. 6-{4,5-dichloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (0.012 g, 0.03 mmol) and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 It was prepared through coupling of (18),2(6),4,14,16-pentaen-8-one (0.011 g, 0.03 mmol). MS m/z = 694.1 (M+H) ⁺

^1H NMR (400MHz, CD ₃ OD) δ 8.88 - 8.83 (m, 2H), 8.75 - 8.71 (m, 1H), 8.10 - 8.08 (m, 1H), 8.02 (s, 1H), 7.76 (s, 1H) ), 7.72 - 7.69 (m, 1H), 7.56 - 7.51 (m, 1H), 6.47 (d, J=0.7 Hz, 1H), 6.08 - 6.00 (m, 1H), 2.80 - 2.63 (m, 1H), 2.36 - 2.16 (m, 1H), 2.11 - 1.96 (m, 2H), 1.67 - 1.42 (m, 2H), 1.06 - 0.95 (d, 3H), 0.71 - 0.53 (m, 1H). Analytical HPLC (Method) A) RT = 13.3 min, purity = 98%; Factor XIa Ki = 11 nM, plasma kallikrein Ki = 4,500 nM.

Example 224

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-4-(1-methyl-1H-imidazol-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] Preparation of octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1 as a peach solid. ,6-dihydropyrimidin-1-yl}-9-methyl-4-(1-methyl-1H-imidazol-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one (21 mg, 18%) was reacted with 5-iodo-1 in a manner similar to the procedure described in Example 216. -Prepared using methyl-1H-imidazole. MS(ESI) m/z: 656.2 (M+H) ⁺ .

^1H NMR (400MHz, CD ₃ OD) δ 9.06 - 9.01 (m, 1H), 8.82 - 8.77 (m, 1H), 8.70 - 8.65 (m, 1H), 8.37 (s, 1H), 8.22 - 8.20 (m , 1H), 7.99 - 7.97 (m, 1H), 7.97 - 7.94 (m, 1H), 7.93 - 7.90 (m, 1H), 7.79 - 7.74 (m, 1H), 7.70 - 7.66 (m, 1H), 7.66 - 7.62 (m, 1H), 6.42 - 6.38 (m, 1H), 6.17 - 6.06 (m, 1H), 3.98 (s, 3H), 2.94 - 2.83 (m, 1H), 2.39 - 2.22 (m, 2H) , 2.12 - 2.00 (m, 1H), 1.81 - 1.69 (m, 1H), 1.68 - 1.54 (m, 1H), 1.13 - 1.05 (m, 3H), 0.87 - 0.74 (m, 1H). Analytical HPLC (Method A): RT = 5.81 min, purity = 91%; Factor XIa Ki = 4.5 nM, plasma kallikrein Ki = 220 nM.

Example 225

4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1 (18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-N-(2,2,2- Preparation of trifluoroethyl)benzamide

225A. Preparation of 4-chloro-2-(6-methoxypyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)benzamide

To RBF was prepared as described in Example 168B 4-chloro-2-(6-methoxypyrimidin-4-yl)benzoic acid (0.374 g, 1.413 mmol), EtOAc (7.07 ml), 2,2,2- CF ₃ CH ₂ NH ₂ (0.14 g, 1.413 mmol), and pyridine (0.229 ml, 2.83 mmol) were added. The solution was cooled in MeOH/ice bath and dissolved in 50% w/w 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6- in EtOAc. Trioxide (1.26 ml, 2.120 mmol) was added. The reaction was allowed to warm to room temperature. After 18 hours, the reaction was diluted with EtOAc, washed with saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated. DCM (~10ml) was added and a few drops of MeOH were added to give a yellow suspension. The solid was filtered, and the filtrate was purified by normal phase chromatography to obtain 4-chloro-2-(6-methoxypyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)benzamide. (0.155 g, 32% yield) was obtained as a white solid. MS(ESI) m/z: 346.4 (M+H) ⁺ .

225B. Preparation of 4-chloro-2-(6-hydroxypyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)benzamide

A solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)benzamide (0.05 g, 0.145 mmol) in ACN (0.96 ml) TMSI (0.118 ml, 0.868 mmol) was added. The reaction was heated to 50°C. After 6 hours, the reaction was cooled to room temperature, then poured into 10% aqueous Na ₂ S ₂ O ₃ and extracted with EtOAc (3x). The combined organic layers were washed with saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purified by normal phase chromatography, 4-chloro-2-(6-hydroxypyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)benzamide (0.02 g, 42% yield) was obtained as a white solid. MS(ESI) m/z: 332.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.14 (d, J=0.9 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.59 - 7.55 (m, 1H), 7.54 - 7.49 (m, 1H), 6.63 (d, J=0.9 Hz, 1H), 3.98 (q, J=9.5 Hz, 2H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -73.22 (s).

225C. 4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-N-(2,2,2- Preparation of trifluoroethyl)benzamide trifluoroacetate

4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1 (18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-N-(2,2,2- Trifluoroethyl)benzamide trifluoroacetate (4.8 mg, 11% yield) was purified from 6-{5-chloro-2-[4-(trifluoromethyl)-1H in a manner similar to the procedure described in Example 56. -1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol to 4-chloro-2-(6-hydroxypyrimidin-4-yl)-N-(2,2,2 It was prepared by replacing -trifluoroethyl)benzamide (0.02 g, 0.060 mmol). MS(ESI) m/z: 614.5 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.95 (s, 1H), 8.73 (d, J=5.3 Hz, 1H), 7.72 -7.71 (m, 2H), 7.59 - 7.55 (m, 1H), 7.54 - 7.48 (m, 3H), 6.66 (s, 1H), 6.05 (dd, J=12.5, 4.2 Hz, 1H), 4.08 - 3.90 (m, 5H), 2.76 - 2.67 (m, 1H), 2.39 - 2.28 ( m, 1H), 2.15 - 1.98 (m, 2H), 1.68 - 1.42 (m, 2H), 1.01 (d, J=7.0 Hz, 3H), 0.79 - 0.62 (m, 1H). ¹⁹ F NMR (376 MHz, CD ₃ OD) δ -73.10 (s), -77.67 (s). Analytical HPLC (Method A): RT = 6.78 min, 98.2% purity; Factor XIa Ki = 23 nM, plasma kallikrein Ki = 3,400 nM.

Example 226

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),3, Preparation of 14,16-pentaen-8-one

226A. N-[(1S)-1-[4-(5-amino-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]but-3-en-1-yl]carbamate manufacturing

(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronic acid (500 mg, 1.712 mmol) in a microwave vial. , 4-bromo-1-methyl-1H-pyrazol-5-amine (301 mg, 1.712 mmol), (DtBPF)PdCl ₂ (55.8 mg, 0.086 mmol), 3 MK ₃ PO ₄ (1.712 mL, 5.13 mmol) ), and THF (18 mL) were added. The reaction mixture was purged with Ar (3x) and then heated in the microwave at 130° C. for 30 min. The reaction mixture was then cooled to room temperature, diluted with EtOAc and washed with brine (2 x 15 mL). The crude product was then subjected to silica gel chromatography to obtain N-[(1S)-1-[4-(5-amino-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]but- 3-en-1-yl]carbamate (0.5 g, 1.383 mmol, 81% yield) was obtained. MS(ESI) m/z: 344.5 (M+H) ⁺ .

226B. (9R,13S)-13-amino-5,9-dimethyl-4,5,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),3 Preparation of ,14,16-pentaen-8-one

(9R,13S)-13-amino-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),3 ,14,16-pentaen-8-one (83 mg, 0.263 mmol, 88% yield) was purified from N-[(1S)-1-[4-(5- amino-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]but-3-en-1-yl]carbamate and the remainder of the sequence as described in the preparation of intermediate 32. Manufacturing continued.

226C. (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-5,9-dimethyl-4,5,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),3, Preparation of 14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),3, 14,16-pentaen-8-one trifluoroacetate (24 mg, 0.032 mmol, 34% yield) was prepared as described in Intermediate 9 in a manner similar to the procedure described in Example 56. -2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (28.8 mg, 0.094 mmol), and (9R,13S)-13-amino- 5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),3,14,16-pentaene-8- It was prepared using on (28.0 mg, 0.094 mmol).

¹ H NMR (400MHz, CD ₃ OD) δ 8.56 (d, J=5.7 Hz, 2H), 8.37 (s, 1H), 8.05 (br. s., 1H), 7.95 (br. s., 1H), 7.89 (d, J=2.4 Hz, 1H), 7.78 - 7.71 (m, 1H), 7.69 - 7.61 (m, 2H), 6.40 (s, 1H), 5.94 (br. s., 1H), 3.82 (s , 3H), 2.88 (d, J=18.3 Hz, 1H), 2.36 (br. s., 1H), 2.29 - 2.07 (m, 2H), 1.76 (d, J=7.3 Hz, 1H), 1.55 (br. . s., 1H), 1.15 (br. s., 3H), 1.00 (br. s., 1H). MS(ESI) m/z: 590.5 [M+H] ⁺ . Analytical HPLC (Method A): RT = 7.04 min, purity = >95.0%; Factor XIa Ki = 106 nM.

Example 227

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-5,9-dimethyl-4,5,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6) Preparation of 3,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-5,9-dimethyl-4,5,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2( 6),3,14,16-pentaen-8-one trifluoroacetate (21 mg, 0.027 mmol, 29% yield) was purified from 6-(5-chloro-2-) in a manner similar to the procedure described in Example 226. (4-Chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol was reacted with 6-(5-chloro-2-(4-() prepared as described in Intermediate 15. It was prepared by replacing with trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (32.0 mg, 0.094 mmol).

^1H NMR (400MHz, CD ₃ OD) δ 8.84 (s, 1H), 8.55 - 8.42 (m, 2H), 8.02 (br. s., 1H), 7.97 - 7.86 (m, 2H), 7.78 - 7.71 ( m, 1H), 7.70 - 7.59 (m, 2H), 6.44 (s, 1H), 5.93 (br. s., 1H), 3.79 (s, 3H), 2.99 - 2.81 (m, 1H), 2.32 (br. s., 1H), 2.26 - 2.04 (m, 2H), 1.73 (d, J=7.3 Hz, 1H), 1.52 (br. s., 1H), 1.26 - 1.07 (m, 3H), 0.99 (br .s., 1H). MS(ESI) m/z: 624.5 [M+H] ⁺ . Analytical HPLC (Method A): RT = 7.83 min, purity = >95.0%; Factor XIa Ki = 97 nM.

Example 228

(9R,13S)-13-[4-(1-benzyl-5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3- (difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16- Preparation of pentaen-8-one

228A. Preparation of 6-(1-benzyl-5-chloro-1H-indazol-7-yl)pyrimidin-4-ol

6-(1-Benzyl-5-chloro-1H-indazol-7-yl)pyrimidin-4-ol (32 mg, 32%) was prepared in a similar manner to intermediate 22 by replacing MeI with BnBr. MS(ESI) m/z: 337 (M+H) ⁺ and 339 (M+2+H) ⁺ .

228B. (9R,13S)-13-[4-(1-benzyl-5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3- (difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16- Preparation of pentaen-8-one trifluoroacetate

(9R,13S)-13-[4-(1-benzyl-5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3- (difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16- Pentaen-8-one trifluoroacetate (4 mg, 9.7%) was reacted with 6-(1-benzyl-5-chloro-1H-indazol-7-yl)pyrimidine-4- in a manner similar to Example 56. (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ² prepared as described in All and Intermediate 30 ^,6 ]Octadeca-1(18),2(6),4,14,16-pentaen-8-one was used to prepare it. MS(ESI) m/z: 655 (M+H) ⁺ , and 657 (M+2+H) ⁺ .

^1H NMR (400MHz, methanol-d4) d 8.99 (s, 1H), 8.69 (d, J=5.1 Hz, 1H), 8.47 - 8.39 (m, 1H), 8.28 (d, J=2.0 Hz, 1H) , 8.11 (s, 1H), 7.89 - 7.82 (m, 1H), 7.72 (d, J=13.6 Hz, 2H), 7.41 (d, J=5.1 Hz, 1H), 7.35 - 7.21 (m, 4H), 6.05 - 5.94 (m, 1H), 5.65 (s, 2H), 2.65 (d, J=6.2 Hz, 1H), 2.40 - 2.30 (m, 1H), 2.07 - 1.92 (m, 2H), 1.56 - 1.33 ( m, 3H), 0.90 (d, J=7.0 Hz, 3H), 0.53 (br. s., 1H). Analytical HPLC (Method A): RT = 10.76 min, purity = >95%; Factor XIa Ki = 110 nM.

Example 229

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, 6] octadeca-1(18),2(6),4, Preparation of 14,16-pentaen-8-one

229A. Preparation of 6-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-ol

6-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-ol (53 mg, 50% Yield) of 1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carboniyl in a manner similar to the procedure described for Intermediate 18C. Tril was dissolved in 4-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxy-5-methylpyrimidine (0.110 g , 0.294 mmol). MS(ESI) m/z: 560.4 (M+H) ⁺ .

229B. Preparation of 6-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-ol

6-(5-chloro-2-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidin-4-ol in THF (5 mL) To a solution of (53 mg, 0.147 mmol) was added 1 M TBAF (0.162 mL, 0.162 mmol) in THF at room temperature. After 3 hours, the solution was concentrated, partitioned between EtOAc and water, and the layers were separated. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were concentrated and then purified by normal phase chromatography to obtain 6-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)-5-methylpyrimidine-4. -ol (14 mg, 33% yield) was obtained as an orange glass. MS(ESI) m/z:288.4 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.02 (s, 1H), 7.71 (d, J=0.9 Hz, 1H), 7.64 - 7.58 (m, 3H), 7.51 (t, J=1.3 Hz, 1H), 1.76 (s, 3H).

229C. (9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, Preparation of 14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-5-methyl-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4, 14,16-pentaen-8-one trifluoroacetate (13 mg, 37% yield) was purified from 6-{5-chloro-2-[4-(trifluoromethyl) in a manner similar to the procedure described in Example 56. )-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol to 6-(5-chloro-2-(1H-1,2,3-triazol-1-yl ) It was prepared by replacing with phenyl)-5-methylpyrimidin-4-ol (0.014 g, 0.049 mmol). MS(ESI) m/z: 570.1 (M+H) ⁺ .

^1H NMR (400MHz, CD ₃ OD) δ8.89 (s, 1H), 8.76 (d, J=5.5 Hz, 1H), 8.17 (d, J=0.9 Hz, 1H), 7.84 (s, 1H), 7.80 - 7.71 (m, 3H), 7.70 - 7.64 (m, 2H), 7.51 (s, 1H), 5.93 (dd, J=12.5, 4.2 Hz, 1H), 4.07 (s, 3H), 2.70 (td, J=6.8, 3.3 Hz, 1H), 2.36 (ddt, J=12.6, 8.4, 4.3 Hz, 1H), 2.14 - 2.00 (m, 2H), 1.69 (s, 3H), 1.66 - 1.55 (m, 1H) , 1.53 - 1.39 (m, 1H), 1.03 (d, J=7.0 Hz, 3H), 0.79 (m, ¹ H). Analytical HPLC (Method A): RT = 6.51 min, purity = 99%; Factor XIa Ki = 63 nM, plasma kallikrein Ki = 2,200 nM.

Example 230

(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-pyrazol-3-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene Preparation of -8-one

(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-pyrazol-3-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene -8-one trifluoroacetate (1.14 mg, 7% yield) was purified in a similar manner to the procedure described in Example 49, 1-methyl-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-1H-pyrazole is converted to 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) It was prepared by replacing -1H-pyrazole (7.61 mg, 0.037 mmol). MS(ESI) m/z: 569.5 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.91 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 7.87 (d, J=2.2 Hz, 1H), 7.67 (s, 1H), 7.61 (dd, J=8.3, 2.3 Hz, 1H), 7.52 - 7.47 (m, 2H), 7.46 - 7.42 (m, 2H), 6.26 (d, J=2.0 Hz, 1H), 6.13 (s, 1H), 6.00 - 5.92 (m, 1H), 4.04 (s, 3H), 3.50 (s, 3H), 2.75 - 2.66 (m, 1H), 2.35 - 2.24 (m, 1H), 2.13 - 1.94 (m, 2H), 1.65 - 1.42 (m, 2H), 1.00 (d, J=6.8 Hz, 3H), 0.76 - 0.60 (m, 1H). Analytical HPLC (Method A): RT = 7.34 min, 98.4% purity; Factor XIa Ki = 800 nM.

Example 231

(9R,13S)-13-{4-[5-chloro-2-(1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3 ,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one manufacture of

1H-imidazole (8.86 mg, 0.130 mmol) and (9R,13S)-13-[4-(5-chloro-2-iodophenyl)- prepared as described in Example 211 in DMSO (1 ml) 6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18 ), 2(6),4,14,16-pentaen-8-one trifluoroacetate (0.02 g, 0.033 mmol) in a solution of CuI (0.62 mg, 3.25 μmol), L-proline (0.75 mg, 6.51 mg) μmol), and K ₂ CO ₃ (0.013 g, 0.098 mmol) were added. The reaction was heated at 80° C. for 3 hours and cooled to room temperature. Purified by reverse phase chromatography, (9R,13S)-13-{4-[5-chloro-2-(1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidine -1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16 -Pentaen-8-one trifluoroacetate (11 mg, 43% yield) was obtained as a yellow solid. MS(ESI) m/z: 555.5 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 9.19 (s, 1H), 8.77 - 8.67 (m, 2H), 7.92 (d, J=2.5 Hz, 1H), 7.81 - 7.75 (m, 1H), 7.73 - 7.64 (m, 4H), 7.54 - 7.48 (m, 2H), 6.62 (s, 1H), 6.00 - 5.91 (m, 1H), 4.04 (s, 3H), 2.74 - 2.64 (m, 1H), 2.32 - 2.21 (m, 1H), 2.11 - 1.92 (m, 2H), 1.64 - 1.39 (m, 2H), 1.01 (d, J=6.9 Hz, 3H), 0.79 - 0.63 (m, 1H). Analytical HPLC (Method A): RT = 4.41 min, 99.9% purity; Factor XIa Ki = 23 nM, plasma kallikrein Ki = 1,100 nM.

Example 232

(9R,13S)-13-[4-(5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoro Methyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8 -manufacture of

232A. Preparation of 6-(5-chloro-1H-indazol-7-yl)pyrimidin-4-ol

6-(5-Chloro-1H-indazol-7-yl)pyrimidin-4-ol (13.8 mg, 17%) was reacted with 4-bromo-6-chloro-1H-benzo[ in a manner similar to Example 207C. d]Prepared starting from 7-bromo-5-chloro-1H-indazole instead of imidazole. MS(ESI) m/z: 247 (M+H) ⁺ and 249 (M+2+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.41 (d, J=0.9 Hz, 1H), 8.15 (s, 1H), 8.02 (d, J=1.8 Hz, 1H), 7.99 (d, J=1.8 Hz, 1H), 7.14 (d, J=0.7 Hz, 1H).

232B. (9R,13S)-13-[4-(5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoro methyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaene-8 -Manufacture of trifluoroacetate.

(9R,13S)-13-[4-(5-chloro-1H-indazol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoro Methyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8 -one trifluoroacetate (5 mg, 13%) was reacted with 6-(5-chloro-1H-indazol-7-yl)pyrimidin-4-ol in a manner similar to Example 56 and as described in Intermediate 30. Prepared (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( It was prepared using 18),2(6),4,14,16-pentaen-8-one. MS(ESI) m/z: 565 (M+H) ⁺ and 567 (M+2+H) ⁺ .

^1H NMR (400MHz, DMSO-d ₆ ) d 13.40 (br. s., 1H), 9.37 (s, 1H), 9.00 (s, 1H), 8.70 (d, J=5.1 Hz, 1H), 8.14 ( br. s., 1H), 8.07 - 8.02 (m, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.93 - 7.74 (m, 2H), 7.69 (s, 1H), 7.38 (d, J =5.1 Hz, 1H), 7.19 (br. s., 1H), 5.93 (d, J=9.5 Hz, 1H), 2.65 - 2.60 (m, 1H), 2.26 (d, J=1.8 Hz, 1H), 2.06 - 1.91 (m, 2H), 1.49 - 1.30 (m, 2H), 0.83 (d, J=6.8 Hz, 3H), 0.35 (br. s., 1H). Analytical HPLC (Method A): RT = 11.43 min, purity = >95%; Factor XIa Ki = 110 nM, plasma kallikrein Ki = 4,300 nM.

Example 233

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-4-(6-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-4-(6-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- 1(18),2,5,14,16-pentaen-8-one was prepared using 5-iodo-2-methoxypyridine in a manner similar to the procedure described in Example 216 to give (9R,13S) -13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-4-(6-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18), 2,5,14,16-pentaen-8-one trifluoroacetate was obtained as a brown solid (12 mg, 23%). MS(ESI) m/z: 683.5 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.74 - 8.69 (m, 1H), 8.68 - 8.62 (m, 2H), 8.36 (d, J=7.4 Hz, 2H), 8.21 - 8.14 (m, 1H), 8.02 - 7.97 (m, 1H), 7.92 (d, J=2.2 Hz, 1H), 7.75 (d, J=2.5 Hz, 2H), 7.67 (d, J=8.5 Hz, 1H), 7.01 - 6.94 (m , 1H), 6.41 (d, J=0.8 Hz, 1H), 6.13 - 6.03 (m, 1H), 4.00 (s, 3H), 2.90 - 2.81 (m, 1H), 2.38 - 2.22 (m, 2H), 2.05 (s, 1H), 1.81 - 1.69 (m, 1H), 1.64 - 1.52 (m, 1H), 1.40 - 1.28 (m, 1H), 1.11 (d, J=6.9 Hz, 3H). Analytical HPLC (Method A): RT = 9.08 min, purity = 95%; Factor XIa Ki = 1.1 nM, plasma kallikrein Ki = 16 nM.

Example 234

(10R,14S)-3-Chloro-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1 ,6-dihydropyrimidin-1-yl}-10-methyl-5,8-diazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2(7),3,5, Preparation of 15,17-hexaen-9-one

(10R,14S)-3-chloro-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1 ,6-dihydropyrimidin-1-yl}-10-methyl-5,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5, 15,17-hexaen-9-one trifluoroacetate (0.0069 g, 44%) was prepared as described in Intermediate 38 according to the procedure described in Example 206 (10R,14S)-14-amino-3- Chloro-10-methyl-5,8-diazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one was prepared by replacing 2-bromopyridin-3-amine with 4-bromo-5-chloropyridin-3-amine in intermediate 38B. MS(ESI) m/z: 620.1 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD, 60℃) δ 9.00 (s, 1H), 8.75 (s, 1H), 8.71 - 8.60 (m, 1H), 8.56 (s, 1H), 8.16 (d, J= 2.5 Hz, 1H), 8.03 (dd, J=8.4, 2.3 Hz, 1H), 7.97 - 7.82 (m, 4H), 7.73 (br. s., 1H), 6.70 (s, 1H), 6.04 (dd, J=12.8, 3.2 Hz, 1H), 2.73 - 2.55 (m, 2H), 2.52 - 2.41 (m, 1H), 2.00 (d, J=9.1 Hz, 2H), 1.85 - 1.58 (m, 1H), 1.47 (d, J=6.6 Hz, 3H), 1.45 - 1.23 (m, 1H). Analytical HPLC (Method A): RT = 9.14 min, purity >99%; Factor XIa Ki = 0.29 nM, plasma kallikrein Ki = 80 nM.

Example 235

(9R,13S)-13-{4-[5-chloro-2-(1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3 ,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one manufacture of

(9R,13S)-13-{4-[5-chloro-2-(1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3 ,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one Trifluoroacetate (2.97 mg, 14% yield) was reacted with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabo in a manner similar to the procedure described in Example 49. Rolan-2-yl)-1H-pyrazole is converted to tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole- It was prepared by replacing with 1-carboxylate (14.35 mg, 0.049 mmol). MS(ESI) m/z: 555.5 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.97 (s, 1H), 8.75 (d, J=5.1 Hz, 1H), 7.70 (s, 1H), 7.57 - 7.47 (m, 7H), 6.37 (s, 1H), 6.02 (dd, J=12.5, 4.4 Hz, 1H), 4.05 (s, 3H), 2.76 - 2.67 (m, 1H), 2.39 - 2.28 (m, 1H), 2.15 - 1.98 (m, 2H) , 1.67 - 1.43 (m, 2H), 1.01 (d, J=7.0 Hz, 3H), 0.80 - 0.63 (m, 1H). Analytical HPLC (Method A): RT = 6.50 min, 99.7% purity; Factor XIa Ki = 14 nM, plasma kallikrein Ki = 550 nM.

Example 236

N-benzyl-4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] Preparation of octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}benzamide

To a cooled (0° C.) solution of phenylmethanamine (0.081 ml, 0.741 mmol) in DCE (1.48 ml) was added dropwise 2.0 M Al(Me) ₃ in hexane (0.36 ml, 0.72 mmol). A white plume of gas formed in the reaction mixture. Gas evolution was observed in solution. The resulting clear solution was stirred at 0°C for 15 minutes and then warmed to room temperature for 2 hours. Next, methyl 4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7 prepared as described in Example 168 in DCE (1 ml) ,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6- A solution of dihydropyrimidin-4-yl}benzoate (0.049 g, 0.074 mmol) was added and the resulting clear yellow reaction was heated to 40°C. After 5 hours, the reaction was cooled to room temperature and the reaction was added to a cold (0° C.), vigorously stirred suspension of DCM/saturated Rochelle salt. The biphasic mixture was stirred for 10-15 minutes and then the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with 1.0 N HCl, brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purified by reverse phase chromatography, N-benzyl-4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[ 12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl }Benzamide trifluoroacetate (6 mg, 11% yield) was obtained as a yellow solid. MS(ESI) m/z: 622.6 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.80 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 7.55 - 7.49 (m, 4H), 7.34 - 7.15 (m, 5H), 6.66 (s, 1H), 6.02 (dd, J=12.5, 4.2 Hz, 1H), 4.51 - 4.39 (m, 2H), 4.05 (s, 3H), 2.78 - 2.67 (m, 1H), 2.34 - 2.21 (m, 1H), 2.16 - 2.05 (m, 1H), 2.03 - 1.92 (m, 1H), 1.69 - 1.42 (m, 2H), 1.02 (d, J= 6.8 Hz, 3H), 0.77 - 0.59 (m, 1H). Analytical HPLC (Method A): RT = 7.27 min, 97.9% purity; Factor XIa Ki = 23 nM, plasma kallikrein Ki = 1,600 nM.

Example 237

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-4-(pyridin-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of 2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-methyl-4-(pyridin-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18) , 2,5,14,16-pentaen-8-one was prepared using 2-iodopyridine in a manner similar to the procedure described in Example 216 to give (9R,13S)-13-{4-[5- Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4 -(pyridin-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaene-8- Monotrifluoroacetate (44 mg, 47%) was obtained. MS(ESI) m/z: 653.5 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.56 - 9.54 (m, 1H), 9.54 (s, 1H), 8.80 (s, 1H), 8.73 - 8.73 (m, 1H), 8.75 (s, 1H) , 8.68 (s, 1H), 8.64 (d, J=5.2 Hz, 1H), 8.53 (d, J=4.9 Hz, 1H), 8.12 - 8.02 (m, 2H), 8.00 - 7.90 (m, 2H), 7.88 - 7.81 (m, 1H), 7.81 - 7.72 (m, 1H), 7.63 (dd, J=5.0, 1.1 Hz, 1H), 7.49 - 7.39 (m, 1H), 6.39 (s, 1H), 6.12 - 5.95 (m, 1H), 2.88 - 2.73 (m, 1H), 2.40 - 2.22 (m, 2H), 1.92 - 1.78 (m, 1H), 1.64 - 1.51 (m, 1H), 1.50 - 1.37 (m, 1H) ), 0.95 (d, J=6.7 Hz, 3H), 0.65 - 0.40 (m, 1H). Analytical HPLC (Method C): RT = 1.75 min, purity = 100%; Factor XIa Ki = 8 nM, plasma kallikrein Ki = 150 nM.

Example 238

1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-( ^2H ₃ )methyl-9-methyl-8-oxo-3,4,7,15-tetra Azatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidine Preparation of -4-yl}phenyl)-1H-pyrazole-4-carbonitrile

238A. Preparation of 4-(3-chloro-2-fluoro-6-iodophenyl)-6-methoxypyrimidine

pTsOH·H ₂ O in a suspension of 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (2 g, 7.88 mmol) in CH ₃ CN (90 ml) at 0°C. (3.75 g, 19.71 mmol) was added, followed by a solution of NaNO ₂ (1.088 g, 15.77 mmol) and NaI (2.95 g, 19.71 mmol) in water (22.5 ml) dropwise. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated NaHCO ₃ and extracted with EtOAc. The organic layer was washed with saturated Na ₂ S ₂ O ₃ , brine, dried over MgSO ₄ , filtered and concentrated. Purification by normal phase chromatography gave 4-(3-chloro-2-fluoro-6-iodophenyl)-6-methoxypyrimidine (2.18 g, 76% yield) as a viscous yellow oil. MS(ESI) m/z: 365.1 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.92 (d, J=0.9 Hz, 1H), 7.68 (dd, J=8.4, 1.5 Hz, 1H), 7.20 (dd, J=8.5, 7.4 Hz, 1H), 6.78 (s, 1H), 4.07 (s, 3H).

238B. Preparation of 6-(3-chloro-2-fluoro-6-iodophenyl)pyrimidin-4-ol

TMSI (0.411 ml, 3.02 mmol) was added to a suspension of 4-(3-chloro-2-fluoro-6-iodophenyl)-6-methoxypyrimidine (0.22 g, 0.603 mmol) in ACN (6.03 ml). Added. The resulting clear yellow solution was heated to 50° C. for 15 hours. Additional TMSI (0.4 ml) was added and the reaction was heated at 50° C. for 7 hours. The reaction was poured into 10% Na ₂ S ₂ O ₃ and saturated NaHCO ₃ and extracted with EtOAc (2x), and a mixture of DCM and MeOH. The organic layers were combined and concentrated. Purification by normal phase chromatography gave 6-(3-chloro-2-fluoro-6-iodophenyl)pyrimidin-4-ol (190 mg, 90% yield) as a yellow glass. MS(ESI) m/z: 351.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.33 (d, J=1.1 Hz, 1H), 7.77 (dd, J=8.6, 1.5 Hz, 1H), 7.34 (dd, J=8.6, 7.5 Hz, 1H) , 6.51 (d, J=0.9 Hz, 1H), 4.85 (br. s., 1H).

238C. Preparation of 1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-pyrazole-4-carbonitrile

1H-pyrazole-4-carbonitrile (50.5 mg, 0.542 mmol), K ₃ PO ₄ (233 mg, 1.084 mmol) and 6-(3-chloro-2-fluoro-6- in dioxane (0.24 mL) To a suspension of iodophenyl)pyrimidin-4-ol (190 mg, 0.542 mmol) was added (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (38.6 mg, 0.271 mmol). The vial was then purged with Ar, CuI (5.16 mg, 0.027 mmol) was added and the vial was sealed. The reaction mixture was heated at 80°C. After 16 hours, the reaction was cooled to room temperature, filtered, and the filtrate was concentrated. Purified by reverse phase chromatography, 1-(4-chloro-3-fluoro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-pyrazole-4-carbonitrile (74 mg, 43 % yield) was obtained as an off-white solid. MS(ESI) m/z: 316.3 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.54 (s, 1H), 8.09 (d, J=0.9 Hz, 1H), 7.97 (s, 1H), 7.80 (dd, J=8.7, 7.8 Hz, 1H) , 7.50 (dd, J=8.7, 1.7 Hz, 1H), 6.51 (t, J=1.1 Hz, 1H).

238D. 1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-( ^2H ₃ )methyl-9-methyl-8-oxo-3,4,7,15-tetra Azatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidine -4-yl}phenyl)-1H-pyrazole-4-carbonitrile, preparation of trifluoroacetate

1-(4-chloro-3-fluoro-2-{1-[(9R,13S)-3-( ^2H ₃ )methyl-9-methyl-8-oxo-3,4,7,15-tetra Azatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidine -4-yl}phenyl)-1H-pyrazole-4-carbonitrile trifluoroacetate (9.5 mg, 41% yield) was purified from 1-(4-chloro-3-fluoroacetic acid) in a manner similar to the procedure described in Example 56. Ro-2-(6-hydroxypyrimidin-4-yl)phenyl)-1H-pyrazole-4-carbonitrile (10 mg, 0.032 mmol) and (9R,13S)- prepared as described in Intermediate 33 13-amino-3-( ^2H3 )methyl-9 _- methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6), Prepared using 4,14,16-pentaen-8-one (9.58 mg, 0.032 mmol). MS(ESI) m/z: 601.0 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.81 (s, 1H), 8.76 (d, J=5.1 Hz, 1H), 8.46 (s, 1H), 7.94 (s, 1H), 7.80 (dd, J= 8.6, 7.7 Hz, 1H), 7.69 (s, 1H), 7.55 - 7.48 (m, 3H), 6.54 (s, 1H), 6.00 (dd, J=13.0, 4.2 Hz, 1H), 2.70 (dt, J =6.7, 3.2 Hz, 1H), 2.36 - 2.25 (m, 1H), 2.15 - 1.95 (m, 2H), 1.67 - 1.55 (m, 1H), 1.55 - 1.41 (m, 1H), 1.01 (d, J =6.8 Hz, 3H), 0.72 (m., 1H). Analytical HPLC (Method A): RT = 7.58 min, purity = 98.5%; Factor XIa Ki = 2.4 nM, plasma kallikrein Ki = 1,500 nM.

Example 239

1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl} Preparation of -3-fluorophenyl)-1H-pyrazole-4-carbonitrile

1-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl} -3-Fluorophenyl)-1H-pyrazole-4-carbonitrile was prepared as described in Intermediate 33 in a manner similar to the procedure described in Example 238 (9R,13S)-13-amino-3-( ² H ₃ )methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene -8-one was reacted with (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[, prepared as described in Example 30G. 12.3.1.0 ^2,6 ] was prepared by replacing it with octadeca-1(18),2(6),4,14,16-pentaen-8-one (10.62 mg, 0.032 mmol). MS(ESI) m/z: 634.0 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.86 (s, 1H), 8.78 (d, J=5.1 Hz, 1H), 8.47 (s, 1H), 7.94 (s, 1H), 7.83 - 7.77 (m, 1H), 7.74 (s, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 7.52 (dd, J=8.7, 1.4 Hz, 2H), 6.55 (s, 1H), 6.01 (dd, J =12.7, 4.1 Hz, 1H), 2.76 - 2.65 (m, 1H), 2.31 (t, J=13.0 Hz, 1H), 2.10 - 1.95 (m, 2H), 1.65 - 1.42 (m, 2H), 1.00 ( d, J=7.0 Hz, 3H), 0.67 (m., 1H). Analytical HPLC (Method A): Sunfire, RT = 8.75 min, 98.8% purity; Factor XIa Ki = 1.0 nM, plasma kallikrein Ki = 1,100 nM.

Example 240

(9R,13S)-13-{4-[5-chloro-2-(1-propyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene Preparation of -8-one

(9R,13S)-13-{4-[5-chloro-2-(1-propyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene -8-one trifluoroacetate (14.3 mg, 62% yield) was purified from 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2) in a manner similar to the procedure described in Example 49. -dioxaborolan-2-yl)-1H-pyrazole is reacted with 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- It was prepared by replacing with 1H-pyrazole (11.52 mg, 0.049 mmol). MS(ESI) m/z: 597.4 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.01 (s, 1H), 8.75 (d, J=5.1 Hz, 1H), 7.74 (s, 1H), 7.58 - 7.52 (m, 3H), 7.50 - 7.47 ( m, 3H), 7.42 (s, 1H), 6.40 (d, J=0.4 Hz, 1H), 6.02 (dd, J=12.7, 4.3 Hz, 1H), 4.07 - 4.01 (m, 5H), 2.76 - 2.67 (m, 1H), 2.40 - 2.29 (m, 1H), 2.13 - 2.00 (m, 2H), 1.77 (sxt, J=7.2 Hz, 2H), 1.67 - 1.43 (m, 2H), 1.02 (d, J =6.8 Hz, 3H), 0.79 (t, J=7.4 Hz, 3H), 0.75 - 0.66 (m, 1H). Analytical HPLC (Method A): RT = 8.12 min, 100% purity; Factor XIa Ki = 35 nM, plasma kallikrein Ki = 3,800 nM.

Example 241

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-4-(pyridin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of 2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-methyl-4-(pyridin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18) , 2,5,14,16-pentaen-8-one was prepared using 4-iodopyridine in a manner similar to the procedure described in Example 216 to give (9R,13S)-13-{4-[5- Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4 -(pyridin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaene-8- One trifluoroacetate (29 mg, 30% yield) was obtained. MS(ESI) m/z: 653.6 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.57 (s, 1H), 8.86 (s, 1H), 8.72 (s, 1H), 8.67 (s, 1H), 8.58 (d, J=4.9 Hz, 1H ), 8.04 (br. s., 2H), 7.91 - 7.82 (m, 2H), 7.80 - 7.73 (m, 1H), 7.73 - 7.65 (m, 1H), 7.57 (d, J=5.2 Hz, 1H) , 6.31 (s, 1H), 6.01 - 5.87 (m, 1H), 2.80 - 2.67 (m, 1H), 2.22 (d, J=7.3 Hz, 2H), 1.80 (br. s., 1H), 1.59 - 1.45 (m, 1H), 1.44 - 1.29 (m, 1H), 0.87 (d, J=7.0 Hz, 3H), 0.59 - 0.36 (m, 1H). Analytical HPLC (Method C): RT = 1.42 min, purity = 98%; Factor XIa Ki = 0.58 nM, plasma kallikrein Ki = 20 nM.

Example 242

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-3-(pyridin-4-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) Preparation of ,2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-methyl-3-(pyridin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18) ,2(6),4,14,16-pentaen-8-one (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3- triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(pyridin-4-yl)-3,4,7,15- A side product ( ² mg, 2.4%). MS(ESI) m/z: 653.6 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 8.98 (br. s., 1H), 8.74 (br. s., 2H), 8.65 (br. s., 3H), 8.03 - 7.91 (m, 3H) , 7.88 - 7.66 (m, 5H), 6.41 (br. s., 1H), 5.91 - 5.79 (m, 1H), 3.90 (br. s., 1H), 3.45 (br. s., 2H), 2.41 - 2.30 (m, 2H), 2.10 - 2.04 (m, 1H), 2.03 - 1.95 (m, 1H), 1.94 - 1.81 (m, 2H), 1.67 (br. s., 2H), 1.54 (br. s. ., 3H), 1.30 (br. s., 4H), 1.21 (br. s., 4H). Analytical HPLC (Method C): RT = 1.37 min, purity = 100%; Factor XIa Ki = 22 nM, plasma kallikrein Ki = 470 nM.

Example 243

1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imidazole -Manufacture of 4-carbonitrile

1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imidazole -4-Carbonitrile trifluoroacetate (9.7 mg, 37% yield) was reacted with 1H-imidazole to 1H-imidazole-4-carbonitrile (0.012 g, 0.130 mmol) in a manner similar to the procedure described in Example 231. It was manufactured as a replacement. MS(ESI) m/z: 580.20 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.22 (s, 1H), 8.82 (s, 1H), 8.69 (d, J=5.2 Hz, 1H), 8.29 (s, 1H), 8.04 (s, 1H) ), 7.88 (d, J=2.4 Hz, 1H), 7.78 (dd, J=8.5, 2.1 Hz, 1H), 7.70 - 7.66 (m, 2H), 7.59 (d, J=4.9 Hz, 1H), 7.48 (s, 1H), 6.37 (s, 1H), 5.89 (d, J=10.7 Hz, 1H), 4.01 (s, 3H), 2.69 - 2.61 (m, 1H), 2.39 - 2.27 (m, 1H), 2.11 (t, J=12.5 Hz, 1H), 1.89 - 1.80 (m, 1H), 1.53 - 1.42 (m, 1H), 1.39 - 1.29 (m, 1H), 0.89 (d, J=7.0 Hz, 3H) , 0.50 - 0.34 (m, 1H). Analytical HPLC (Method B): RT = 8.12 min, 100% purity; Factor XIa Ki = 53 nM, plasma kallikrein Ki = 3,400 nM.

Example 244

N-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl} Preparation of phenyl)-2,2,2-trifluoroacetamide

N-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl} Phenyl)-2,2,2-trifluoroacetamide was prepared as described in Intermediate 1 in a manner similar to the procedure described in Example 56. N-(4-chloro-2-(6-hydroxypyrimidine- 4-yl)phenyl)-2,2,2-trifluoroacetamide (0.19 g, 0.60 mmol), and (9R,13S)-13-amino-3-(difluoro) prepared as described in Intermediate 30 Romethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene- Prepared using 8-one (0.20 g, 0.60 mmol), N-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8- Oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6 -Oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide (222 mg, 58%) was obtained as a white powder. MS(ESI) m/z: 636.5 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.23 (s, 1H), 8.89 (s, 1H), 8.56 (d, J=5.1 Hz, 1H), 7.74 - 7.69 (m, 3H), 7.55 (s, 1H), 7.46 - 7.39 (m, 1H), 7.24 (d, J=5.1 Hz, 1H), 6.74 (s, 1H), 5.83 - 5.70 (m, 1H), 2.55 - 2.40 (m, 1H), 2.27 - 2.12 (m, 1H), 1.89 (s, 1H), 1.81 - 1.66 (m, 1H), 1.38 - 1.24 (m, 1H), 1.24 - 1.11 (m, 1H), 0.70 (d, J=7.0 Hz) , 3H). Analytical HPLC (Method A): RT = 10.89 min, purity = 99%; Factor XIa Ki = 3.9 nM, plasma kallikrein Ki = 260 nM.

Example 245

(9R,13S)-13-(4-{5-chloro-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-di Hydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4, Preparation of 14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-di Hydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, 14,16-pentaen-8-one trifluoroacetate (15.5 mg, 67% yield) was purified from 1-methyl-4-(4,4,5,5-tetramethyl) in a manner similar to the procedure described in Example 49. -1,3,2-dioxaborolan-2-yl)-1H-pyrazole is reacted with 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabor) Prepared by replacing rolan-2-yl)-1H-pyrazole (11.52 mg, 0.049 mmol). MS(ESI) m/z: 597.4 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.02 (s, 1H), 8.75 (d, J=5.1 Hz, 1H), 7.74 (s, 1H), 7.62 (s, 1H), 7.56 (dd, J= 5.2, 1.7 Hz, 1H), 7.54 - 7.52 (m, 1H), 7.50 - 7.47 (m, 3H), 7.39 (s, 1H), 6.40 (d, J=0.4 Hz, 1H), 6.02 (dd, J =12.7, 4.3 Hz, 1H), 4.46 (spt, J=6.7 Hz, 1H), 4.05 (s, 3H), 2.76 - 2.66 (m, 1H), 2.41 - 2.30 (m, 1H), 2.14 - 2.00 ( m, 2H), 1.67 - 1.37 (m, 8H), 1.02 (d, J=6.8 Hz, 3H), 0.80 - 0.64 (m, 1H). Analytical HPLC (Method A): RT = 8.07 min, 100% purity; Factor XIa Ki = 44 nM, plasma kallikrein Ki = 5,600 nM.

Example 246

(9R,13S)-13-{4-[5-(difluoromethoxy)-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl] -6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ] Preparation of octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-(difluoromethoxy)-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl] as a solid phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (13 mg, 60% yield) was subjected to HATU,DBU coupling as described in Example 56. Using the methodology 6-[5-(difluoromethoxy)-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl]pyrimidine-4- ol (0.012 g, 0.03 mmol) and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ] prepared through coupling of octadeca-1(18),2(6), 4,14,16-pentaen-8-one (0.011 g, 0.03 mmol). MS m/z = 692.1 (M+H) ⁺

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 9.22 (s, 1H), 8.78 (s, 1H), 8.70 (d, J=5.2 Hz, 1H), 7.97 - 7.81 (m , 1H), 7.71 - 7.64 (m, 2H), 7.59 - 7.53 (m, 2H), 7.50 - 7.46 (m, 1H), 7.45 - 7.41 (m, 1H), 6.47 - 6.41 (m, 1H), 5.95 - 5.85 (m, 1H), 2.71 - 2.59 (m, 1H), 2.35 - 2.23 (m, 1H), 2.07 - 1.98 (m, 1H), 1.90 - 1.74 (m, 1H), 1.52 - 1.24 (m, 2H), 0.88 (d, J=6.7 Hz, 3H), 0.46 - 0.19 (m, 1H). Analytical HPLC (Method B) RT = 1.8 min, purity = 100%; Factor XIa Ki = 110 nM.

Example 247

(9R,13S)-3-(difluoromethyl)-13-(4-{5-methoxy-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1 -yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca -Preparation of 1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-3-(difluoromethyl)-13-(4-{5-methoxy-2-[4-(trifluoromethyl)-1H-1,2,3-triazole as a solid -1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ] Octadeca-1(18),2(6),4,14,16-pentaen-8-one (12 mg, 50% yield) was purified using the HATU, DBU coupling methodology as described in Example 56. 6-{5-methoxy-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (0.012 g, 0.03 mmol) and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18 ), 2(6), and 4,14,16-pentaen-8-one (0.012 g, 0.03 mmol) were prepared through coupling. MS m/z = 656.2 (M+H) ⁺

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.16 - 9.12 (m, 1H), 8.91 - 8.88 (m, 1H), 8.52 - 8.48 (m, 1H), 8.47 - 8.43 (m, 1H), 7.66 - 7.63 (m, 2H), 7.60 - 7.55 (m, 1H), 7.46 - 7.42 (m, 1H), 7.20 - 7.16 (m, 1H), 7.14 - 7.10 (m, 1H), 7.05 - 7.00 (m, 1H) ), 6.21 - 6.12 (m, 1H), 5.72 - 5.54 (m, 1H), 2.46 - 2.38 (m, 1H), 2.09 - 1.98 (m, 1H), 1.86 - 1.69 (m, 1H), 1.63 - 1.47 (m, 1H), 1.29 - 1.00 (m, 2H), 0.65 - 0.58 (d, 3H), 0.20 - 0.04 (m, 1H). Analytical HPLC (Method B) RT = 1.72 min, purity = 100%; Factor XIa Ki = 7.7 nM, plasma kallikrein Ki = 2,400 nM.

Example 248

(9R,13S)-13-(4-{5-chloro-2-[1-(2-methylpropyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydro Pyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14 , Preparation of 16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[1-(2-methylpropyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-dihydro Pyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14 ,16-pentaen-8-one trifluoroacetate (7.6 mg, 32% yield) was purified from 1-methyl-4-(4,4,5,5-tetramethyl-) in a manner similar to the procedure described in Example 49. 1,3,2-dioxaborolan-2-yl)-1H-pyrazole is reacted with 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)-1H-pyrazole (12.20 mg, 0.049 mmol) was substituted. MS(ESI) m/z: 611.4 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.00 (s, 1H), 8.75 (d, J=5.3 Hz, 1H), 7.72 (s, 1H), 7.57 - 7.47 (m, 6H), 7.42 (s, 1H), 6.37 (d, J=0.4 Hz, 1H), 6.02 (dd, J=12.8, 4.2 Hz, 1H), 4.05 (s, 3H), 3.91 - 3.81 (m, 2H), 2.76 - 2.67 (m , 1H), 2.34 (tt, J=12.7, 4.3 Hz, 1H), 2.14 - 1.98 (m, 3H), 1.67 - 1.43 (m, 2H), 1.01 (d, J=6.8 Hz, 3H), 0.83 - 0.63 (m, 7H). Analytical HPLC (Method A): RT = 8.63 min, 100% purity; Factor XIa Ki = 73 nM, plasma kallikrein Ki = 8,900 nM.

Example 249

(9R,13S)-13-{4-[2-(1-benzyl-1H-pyrazol-4-yl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene Preparation of -8-one

(9R,13S)-13-{4-[2-(1-benzyl-1H-pyrazol-4-yl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene -8-one trifluoroacetate (2.68 mg, 11% yield) was purified from 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2) in a manner similar to the procedure described in Example 49. -dioxaborolan-2-yl)-1H-pyrazole is reacted with 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- It was prepared by replacing with 1H-pyrazole (13.86 mg, 0.049 mmol). MS(ESI) m/z: 645.4 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.95 (s, 1H), 8.67 (d, J=5.1 Hz, 1H), 7.70 (s, 1H), 7.59 (s, 1H), 7.54 - 7.45 (m, 6H), 7.29 - 7.19 (m, 3H), 7.09 - 7.05 (m, 2H), 6.36 (d, J=0.7 Hz, 1H), 6.00 (dd, J=12.7, 4.1 Hz, 1H), 5.27 (s) , 2H), 4.02 (s, 3H), 2.77 - 2.68 (m, 1H), 2.34 - 2.23 (m, 1H), 2.15 - 2.05 (m, 1H), 2.01 - 1.90 (m, 1H), 1.67 - 1.42 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.76 - 0.60 (m, 1H). Analytical HPLC (Method A): RT = 8.90 min, 100% purity; Factor XIa Ki = 100 nM.

Example 250

(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, Preparation of 14,16-pentaen-8-one

250A. Preparation of 4-(5-chloro-2-ethynylphenyl)-6-methoxypyrimidine

[4-(5-chloro-2-iodophenyl)-6-methoxypyrimidine (0.520 g, 1.50 mmol), prepared as described in Example 211, and Pd(PPh ₃ ) ₄ (0.087 g, 0.075 mmol) was purged with Ar for several minutes. Next, degassed THF (7.50 ml) and tributylstannylacetylene (0.651 ml, 2.25 mmol) were added. The resulting transparent burgundy colored solution was stirred at room temperature. After 15 hours, the dark purple reaction was diluted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a purple solid. Purification by normal phase chromatography using 0-10% EtOAc/Hex gave 4-(5-chloro-2-ethynylphenyl)-6-methoxypyrimidine (0.176 g, 48%) as an off-white solid. MS(ESI) m/z: 244.9 (M+H) ⁺ .

250B. Preparation of 4-(5-chloro-2-{1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl} phenyl)-6-methoxypyrimidine

TMSN ₃ (0.091 ml, 0.61 mmol), 4-(5-chloro-2-ethynylphenyl)-6-methoxypyrimidine (0.050 g, 0.20 mmol), sodium ascorbate (8.10 mg, 0.041 mmol), and A sealed vial containing a mixture of CuSO ₄ (3.26 mg, 0.020 mmol) was stirred at 60°C. After 2 hours, the dark reaction was cooled to room temperature. The mixture was diluted with EtOAc (15 mL) and the cloudy solution was washed with water (3x), brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 0.110 g of crude product as a black oil. Purified by normal phase chromatography using 0-40% EtOAc/Hex to give 4-(5-chloro-2-{1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl }phenyl)-6-methoxypyrimidine (0.0191 g, 25%) was obtained as a yellow residue. MS(ESI) m/z: 374.0 (M+H) ⁺ .

250C. Preparation of 4-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]-6-methoxypyrimidine

4-(5-chloro-2-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl) in THF (0.508 ml) and water (1.831 μl, 0.102 mmol) To a cooled (0° C.) clear yellow solution of phenyl)-6-methoxypyrimidine (0.019 g, 0.051 mmol) was added dropwise 1.0 M TBAF (0.061 ml, 0.061 mmol) in THF. The reaction was stirred at 0°C for 1 hour and then warmed to room temperature. After 2 hours, additional 1.0 M TBAF (0.061 ml, 0.061 mmol) in THF was added. After 51 hours, additional 1.0 M TBAF (0.51 ml, 0.51 mmol) in THF was added. After 44 hours, the reaction was diluted with EtOAc, washed with saturated NH ₄ Cl, brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 4-(5-chloro-2-(1-methyl-1H- 1,2,3-triazol-4-yl)phenyl)-6-methoxypyrimidine (0.015 g, 98%) was obtained as a yellow residue. MS(ESI) m/z: 302.0 (M+H) ⁺ .

250D. Preparation of 6-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]pyrimidin-4-ol

4-(5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)- in AcOH (0.50 ml) and 48% aqueous HBr (0.28 ml, 2.486 mmol) A clear yellow solution of 6-methoxypyrimidine (0.015 g, 0.050 mmol) was warmed to 85°C. After 1 hour, the reaction was cooled to room temperature and then concentrated to give a brown solid. The brown solid was suspended in EtOAc and filtered to give an off-white solid. Purified by reverse phase chromatography, organo-based with saturated NaHCO ₃ and then 6-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl) phenyl]pyri. Midin-4-ol (0.0090 g, 63%) was obtained as a white solid. MS(ESI) m/z: 288.0 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.21 (s, 1H), 7.90 (s, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.60 (d, J=2.2 Hz, 1H), 7.58 (dd, J=8.3, 2.2 Hz, 1H), 6.38 (s, 1H), 4.09 (s, 3H).

250E. (9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, Preparation of 14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4, 14,16-pentaen-8-one trifluoroacetate (0.0055 g, 25%) was reacted with 6-{5-chloro-2-[4-(trifluoromethyl) in a manner similar to the procedure described in Example 56. -1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol to 6-[5-chloro-2-(1-methyl-1H-1,2,3-triazole- It was prepared by replacing 4-yl)phenyl]pyrimidin-4-ol. MS(ESI) m/z: 570.1 (M+H) ⁺ and 572.0 (M+2+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.94 (s, 1H), 8.75 (d, J=5.2 Hz, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 7.70 (d, J= 8.3 Hz, 1H), 7.63 (d, J=2.2 Hz, 1H), 7.59 - 7.54 (m, 2H), 7.50 (s, 1H), 6.40 (d, J=0.6 Hz, 1H), 6.04 - 5.99 ( m, 1H), 4.08 (s, 3H), 4.05 (s, 3H), 2.76 - 2.67 (m, 1H), 2.40 - 2.29 (m, 1H), 2.15 - 2.01 (m, 2H), 1.68 - 1.56 ( m, 1H), 1.55 - 1.43 (m, 1H), 1.02 (d, J=7.2 Hz, 3H), 0.79 - 0.64 (m, 1H). Analytical HPLC (Method A): RT = 6.30 min, purity = 100%; Factor XIa Ki = 11 nM, plasma kallikrein Ki = 2,000 nM.

Example 251

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-fluoro-10-methyl-5,8,16-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2 (7), Preparation of 3,5,15,17-hexaen-9-one

251A. Preparation of tert-butyl N-(6-fluoro-4-iodopyridin-3-yl)carbamate

BuLi (11.31 ml, 28.3 mmol) was reacted with tert-butyl (6-fluoropyridin-3-yl)carbamate (2 g, 9.42 mmol) and TMEDA (4.27 ml, 28.3 mmol) in Et ₂ O (47.1 ml). was added dropwise to the stirred, cooled (-78°C) solution. The mixture was allowed to warm to -10°C and stirred for 2 hours. The mixture was re-cooled to -78°C and the cooled (-10°C) solution of I ₂ (4.90 g, 19.32 mmol) in Et ₂ O (25 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 2 days. Saturated aqueous NH ₄ Cl was added and the mixture was extracted with Et ₂ O and EtOAc. The combined organic fractions were washed with Na ₂ S ₂ O ₃ , brine, dried over MgSO ₄ , filtered and concentrated to give a brownish oil which was purified by normal phase chromatography to give tert-butyl N-(6- Fluoro-4-iodopyridin-3-yl)carbamate (0.859 g, 27% yield) was obtained. MS(ESI) m/z: 338.9 (M+H) ⁺ .

251B. Preparation of 6-fluoro-4-iodopyridin-3-amine

To a solution of N-(6-fluoro-4-iodopyridin-3-yl)carbamate (400 mg, 1.183 mmol) in DCM (15 mL) was added TFA (4.56 mL, 59.2 mmol). The reaction was stirred at room temperature for 1 hour. Concentration gave 6-fluoro-4-iodopyridin-3-amine.trifluoroacetate (551 mg, 100%) as a light yellow solid. MS(ESI) m/z: 238.9 (M+H) ⁺ .

251C. (10R,14S)-14-amino-4-fluoro-10-methyl-5,8,16-triazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2,4,6 Preparation of 15,17-hexaen-9-one

(10R,14S)-14-amino-4-fluoro-10-methyl-5,8,16-triazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2,4,6 , 15,17-hexaen-9-one was prepared in a manner similar to the procedure described in Intermediate 39, replacing 2-bromopyridin-3-amine with 6-fluoro-4-iodopyridin-3-amine. did. MS(ESI) m/z: 315.4 (M+H) ⁺ .

251D. (10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-fluoro-10-methyl-5,8,16-triazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2 (7), Preparation of 3,5,15,17-hexaen-9-one

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-fluoro-10-methyl-5,8,16-triazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2 (7),3,5,15,17-hexaen-9-one trifluoroacetate (7.3 mg, 33.7% yield) was purified from (10R,14S)-14-amino in a manner similar to the procedure described in Example 56. -4-fluoro-10-methyl-5,8,16-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2,4,6,15,17-hexaene-9 Prepared using -one (8.8 mg, 0.028 mmol).

¹ H NMR (400MHz, CD ₃ OD) δ 8.91 (s, 1H), 8.83 - 8.79 (m, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.13 - 8.09 (m, 1H), 7.89 ( d, J=2.4 Hz, 1H), 7.78 - 7.65 (m, 3H), 7.48 (dd, J=5.1, 1.8 Hz, 1H), 7.37 (d, J=2.2 Hz, 1H), 6.42 (d, J =0.7 Hz, 1H), 6.04 (dd, J=12.5, 4.8 Hz, 1H), 2.79 - 2.65 (m, 1H), 2.27 - 2.14 (m, 1H), 2.07 - 1.92 (m, 2H), 1.60 - 1.37 (m, 2H), 0.95 (d, J=6.8 Hz, 3H), 0.57 (br. s., 1H). MS(ESI) m/z: 639.0 (M+H) ⁺ . Analytical HPLC (Method A): RT = 9.64 min, purity = 100%; Factor XIa Ki = 0.53 nM, plasma kallikrein Ki = 71 nM.

Example 252

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyridin-2-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ] Preparation of octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyridin-2-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2,5,14,16-pentaen-8-one (9.5 mg, 17%) was reacted with 2-iodo-6-mer in a manner similar to the procedure described in Example 216. Toxypyridine (31 mg, 0.131 mmol) and (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2 as described in Example 196 ,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3. It was purified using 1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.04 g, 0.066 mmol). MS(ESI) m/z: 717.4 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.57 (s, 1H), 9.21 (s, 1H), 8.71 (d, J=15.6 Hz, 2H), 8.59 (d, J=5.2 Hz, 1H), 8.03 - 7.90 (m, 3H), 7.90 - 7.74 (m, 2H), 7.68 - 7.49 (m, 2H), 6.83 (d, J=7.9 Hz, 1H), 6.50 (s, 1H), 6.01 (br. s., 1H), 3.98 (s, 3H), 2.79 (br. s., 1H), 2.38 - 2.15 (m, 2H), 1.85 (br. s., 1H), 1.58 (br. s., 1H) ), 1.42 (br. s., 1H), 0.95 (d, J=6.7 Hz, 3H), 0.57 (br. s., 1H). Analytical HPLC (Method C): RT = 2.07 min, purity = 100%; Factor XIa Ki = 23 nM, plasma kallikrein Ki = 1,100 nM.

Example 253

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1- prepared as described in Example 196 yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca- 1(18),2(6),4,14,16-pentaen-8-one (0.02 g, 0.033 mmol), sodium 2-chloro-2,2-difluoroacetate (50 mg, 0.33 mmol) , Cs ₂ CO ₃ (0.021 g, 0.066 mmol), and DMF (2 mL) were added to a 5 mL microwave vial. The reaction was heated to 130° C. in the microwave for 30 minutes. The mixture was concentrated to dryness, and the residue was purified by reverse phase chromatography to obtain (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2, 3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(difluoromethyl)-9-methyl-3,4,7,15 -Tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2,5,14,16-pentaen-8-one (2 mg, 8%) was obtained. MS(ESI) m/z: 660.1 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.54 (s, 1H), 9.21 (s, 1H), 8.70 (s, 1H), 8.58 (d, J=4.9 Hz, 1H), 8.41 (s, 1H) ), 7.96 (br. s., 1H), 7.92 - 7.68 (m, 4H), 7.53 (d, J=4.9 Hz, 1H), 6.49 (s, 1H), 6.12 - 5.90 (m, 1H), 2.85 - 2.69 (m, 1H), 2.24 (d, J=11.9 Hz, 2H), 1.89 - 1.76 (m, 1H), 1.63 - 1.49 (m, 1H), 1.47 - 1.35 (m, 1H), 0.92 (d) , J=6.7 Hz, 3H), 0.61 - 0.38 (m, 1H). Analytical HPLC (Method C): RT = 1.82 min, purity = 100%; Factor XIa Ki = 8 nM, plasma kallikrein Ki = 360 nM.

Example 254

(9R,13S)-13-{4-[5-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, 6] octadeca-1(18),2(6),4,14,16-penta Preparation of en-8-one

(9R,13S)-13-{4-[5-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4,14,16-penta En-8-one trifluoroacetate (10 mg, 43% yield) was purified from 1-methyl-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-1H-pyrazole is reacted with 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1H-pyrazole (11.42 mg, 0.049 mmol) was prepared by replacing it. MS(ESI) m/z: 595.4 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.99 (s, 1H), 8.76 (d, J=5.3 Hz, 1H), 7.73 (s, 1H), 7.64 (s, 1H), 7.57 - 7.52 (m, 2H), 7.50 (s, 1H), 7.47 - 7.46 (m, J=1.1 Hz, 2H), 7.33 (d, J=0.7 Hz, 1H), 6.39 (s, 1H), 6.03 (dd, J=12.5 , 4.2 Hz, 1H), 4.05 (s, 3H), 3.63 - 3.56 (m, 1H), 2.76 - 2.67 (m, 1H), 2.35 (tt, J=12.7, 4.3 Hz, 1H), 2.14 - 2.01 ( m, 2H), 1.67 - 1.44 (m, 2H), 1.04 - 0.97 (m, 7H), 0.79 - 0.64 (m, 1H). Analytical HPLC (Method A): RT = 7.82 min, 99.9% purity; Factor XIa Ki = 8 nM, plasma kallikrein Ki = 1,700 nM.

Example 255

(9R,13S)-13-(4-{5-chloro-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one

255A. 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole manufacturing

Stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.515 mmol) in DMF (1 ml) Cs ₂ CO ₃ (252 mg, 0.773 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.144 ml, 1.031 mmol) were added at room temperature. After stirring at 100° C. for 2 hours, the reaction mixture was evaporated to dryness, partitioned between EtOAc and water, and the layers were separated. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2 ,2,2-trifluoroethyl)-1H-pyrazole (0.111 g, 78% yield) was obtained. MS(ESI) m/z: 277.4 (M+H) ⁺ .

255B. (9R,13S)-13-(4-{5-chloro-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), Preparation of 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-(4-{5-chloro-2-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] Octadeca-1(18),2( 6),4,14,16-pentaen-8-one trifluoroacetate (10.6 mg, 43% yield) was purified by 1-methyl-4-(4,4,5) in a manner similar to the procedure described in Example 49. ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was prepared as described in 255A, 4-(4,4,5,5-tetramethyl-1, It was prepared by replacing 3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (13.47 mg, 0.049 mmol). MS(ESI) m/z: 637.5 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.97 (s, 1H), 8.74 (d, J=5.3 Hz, 1H), 7.74 - 7.67 (m, 2H), 7.56 - 7.49 (m, 6H), 6.40 ( s, 1H), 6.03 (dd, J=12.7, 4.3 Hz, 1H), 4.92 - 4.82 (m, 2H), 4.05 (s, 3H), 2.76 - 2.67 (m, 1H), 2.39 - 2.28 (m, 1H), 2.14 - 1.99 (m, 2H), 1.67 - 1.43 (m, 2H), 1.02 (d, J=7.0 Hz, 3H), 0.79 - 0.64 (m, 1H). Analytical HPLC (Method A): RT = 8.26 min, 99.5% purity; Factor XIa Ki = 52 nM, plasma kallikrein Ki = 5,500 nM.

Example 256

3-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1, 6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2, Preparation of 5,14,16-pentaen-4-yl]benzonitrile

3-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1, 6-dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2, 5,14,16-pentaen-4-yl]benzonitrile trifluoroacetate was prepared in a manner similar to the procedure described in Example 216, using 3-iodobenzonitrile (3.97 mg, 0.017 mmol) to obtain 3 -[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6 -dihydropyrimidin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2,5 ,14,16-pentaen-4-yl]benzonitrile trifluoroacetate (4.5 mg, 33% yield) was obtained.

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.60 (s, 1H), 8.76 - 8.65 (m, 2H), 8.60 (d, J=5.2 Hz, 1H), 8.36 (s, 1H), 8.25 (d , J=8.2 Hz, 1H), 7.93 - 7.86 (m, 2H), 7.84 - 7.69 (m, 4H), 7.63 (d, J=4.3 Hz, 1H), 6.34 (s, 1H), 5.98 (br. s., 1H), 2.78 (br. s., 1H), 2.54 (s, 1H), 2.24 (d, J=7.3 Hz, 2H), 1.85 (br. s., 1H), 1.56 (br. s) ., 1H), 1.41 (br. s., 1H), 0.93 (d, J=6.7 Hz, 3H), 0.55 (br. s., 1H). MS(ESI) m/z: 677.1 [M+H] ⁺ . Analytical HPLC (Method B): RT = 1.91 min, purity = 100.0%; Factor XIa Ki = 2.0 nM, plasma kallikrein Ki = 30 nM.

Example 257

(9R,13S)-13-{4-[5-chloro-2-(5-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene Preparation of -8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(5-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene -8-one trifluoroacetate (2.3 mg, 9% yield) was obtained by replacing 1H-imidazole with 4-methyl-1H-imidazole (10.68 mg, 0.130 mmol) in a manner similar to the procedure described in Example 231. Manufactured. MS(ESI) m/z: 569.20 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.22 (s, 1H), 8.89 (br. s., 1H), 8.78 (s, 1H), 8.67 (d, J=4.9 Hz, 1H), 8.01 ( d, J=2.4 Hz, 1H), 7.86 (dd, J=8.5, 2.1 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.59 (d, J=4.9 Hz, 1H), 7.50 - 7.40 (m, 2H), 6.41 (br. s., 1H), 5.86 (d, J=10.4 Hz, 1H), 4.01 (s, 3H), 2.68 - 2.60 (m, 1H) ), 2.32 - 2.22 (m, 1H), 2.16 - 2.05 (m, 1H), 2.01 (s, 3H), 1.88 - 1.76 (m, 1H), 1.52 - 1.27 (m, 2H), 0.88 (d, J =6.7 Hz, 3H), 0.50 - 0.37 (m, 1H). Analytical HPLC (Method B): RT = 1.49 min, 100% purity; Factor XIa Ki = 7,500 nM.

Example 258

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-4-(1H-pyrazol-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 Preparation of (18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-methyl-4-(1H-pyrazol-3-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1 (18),2,5,14,16-pentaen-8-one trifluoroacetate was reacted with 3-iodo-1-trityl-1H-pyrazole (18.9 mg) in a manner similar to the procedure described in Example 216. , 0.043 mmol) followed by deprotection using 50% TFA and Et ₃ SiH in DCM as a scavenger to give (9R,13S)-13-{4-[5-chloro-2-(4 -chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(1H-pyrazole -3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one trifluo Loacetate (4.8 mg, 3.2 μmol, 6% yield) was obtained.

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 8.76 - 8.69 (m, 1H), 8.57 (d, J=4.9 Hz, 1H), 8.31 (s, 1H), 8.10 (br s., 1H), 7.93 (d, J=2.1 Hz, 1H), 7.88 (s, 1H), 7.82 (dd, J=8.5, 2.1 Hz, 1H), 7.77 - 7.70 (m, 1H), 7.52 (d, J=4.9 Hz, 1H), 7.30 - 7.02 (m, 3H), 6.37 (s, 1H), 5.97 (br. s., 1H), 2.76 (br. s., 1H), 2.27 (d , J=10.7 Hz, 2H), 1.84 (br. s., 1H), 1.55 (br. s., 1H), 1.41 (br. s., 1H), 0.93 (d, J=6.7 Hz, 3H) , 0.56 (br. s., 1H). MS(ESI) m/z: 642.3 [M+H] ⁺ . Analytical HPLC (Method B): RT = 1.51 min, purity = 100.0%; Factor XIa Ki = 0.29 nM, plasma kallikrein Ki = 18 nM.

Example 259

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18 ), Preparation of 2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18 ), 2,5,14,16-pentaen-8-one trifluoroacetate was prepared using 5-iodopyrimidine (21.4 mg, 0.104 mmol) in a manner similar to the procedure described in Example 216 ( 9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydro Pyrimidin-1-yl}-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18) , 2,5,14,16-pentaen-8-one trifluoroacetate (15 mg, 36%) was obtained.

¹ H NMR (400MHz, CD ₃ OD) δ 9.58 (s, 1H), 9.40 (s, 2H), 9.20 (s, 1H), 8.85 - 8.72 (m, 3H), 8.64 (d, J=5.3 Hz, 1H), 7.98 - 7.91 (m, 2H), 7.87 - 7.80 (m, 1H), 7.79 - 7.73 (m, 1H), 7.65 (dd, J=5.1, 1.3 Hz, 1H), 6.39 (s, 1H) , 6.02 (d, J=9.5 Hz, 1H), 2.82 (br. s., 1H), 2.37 - 2.23 (m, 2H), 1.94 - 1.80 (m, 1H), 1.58 (br. s., 1H) , 1.43 (br. s., 1H), 0.99 - 0.91 (d, J=7.0 Hz, 3H), 0.56 (br. s., 1H). MS(ESI) m/z: 654.6 [M+H] ⁺ . Analytical HPLC (Method A): RT = 7.96 min, purity = >95.0%; Factor XIa Ki = 0.63 nM, plasma kallikrein Ki = 17 nM.

Example 260

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-9-methyl-4-(pyrazin-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca Preparation of -1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-9-methyl-4-(pyrazin-2-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca -1(18),2,5,14,16-pentaen-8-one trifluoroacetate (9.0 mg, 34%) was reacted with 2-iodopyrazine (6.75 mg, 0.033 mmol) and (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole- as described in Example 196 1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa It was prepared using deca-1(18),2(6),4,14,16-pentaen-8-one (20.0 mg, 0.033 mmol).

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.60 (s, 1H), 9.33 (s, 1H), 9.22 (s, 1H), 8.76 - 8.65 (m, 2H), 8.63 - 8.56 (m, 2H) , 7.95 (d, J=16.5 Hz, 2H), 7.88 - 7.78 (m, 2H), 7.66 (d, J=4.9 Hz, 1H), 7.27 - 6.98 (m, 1H), 6.49 (s, 1H), 6.03 (d, J=9.5 Hz, 1H), 2.79 (br. s., 1H), 2.37 - 2.18 (m, 2H), 1.83 (br. s., 1H), 1.56 (br. s., 1H) , 1.42 (br. s., 1H), 0.93 (d, J=6.7 Hz, 3H), 0.52 (br. s., 1H). MS(ESI) m/z: 688.0 [M+H] ⁺ . Analytical HPLC (Method B): RT = 1.923 min, purity = >100.0%; Factor XIa Ki = 2.6 nM, plasma kallikrein Ki = 54 nM.

Example 261

(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl)-9 -Preparation of methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

N-(4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7 prepared as described in Example 244 ,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6- Dihydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide (0.2 g, 0.31 mmol) was dissolved in 1.25 M HCl in MeOH (5 ml, 6.25 mmol). The reaction was heated to 75° C. for 1 hour, then cooled to room temperature and concentrated to dryness. The product was purified by recrystallization from CH ₃ CN-H ₂ O to give (9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidine- 1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ,4,14,16-pentaen-8-one (160 mg, 89%) was obtained as a yellow solid. MS(ESI) m/z: 540.5 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.40 (s, 1 H), 9.00 (s, 1 H), 8.75 (d, J=5.09 Hz, 1 H), 7.96 (t, J=57.75 Hz, 1 H), 7.90 (s, 1 H), 7.73 (s, 1 H), 7.46 (d, J=2.49 Hz, 1 H), 7.43 (dd, J=4.92, 0.85 Hz, 1 H), 7.14 ( dd, J=8.80, 2.51 Hz, 1 H), 6.76 (d, J=8.73 Hz, 1 H), 6.70 (s, 1 H), 6.43 (s, 2 H), 5.95 (dd, 12.17, 3.13 Hz) , 1 H), 2.67 (m, 1 H), 2.34 (tm, J=12.83 Hz, 1 H), 2.08 (tm, J=13.09 Hz, 1 H), 1.93 (m, 1 H), 1.48 (m , 1 H), 1.37 (m, 1 H), 0.89 (d, J=6.87 Hz, 3 H), 0.39 (br-s, 1 H). Analytical HPLC (Method A): RT = 7.75 min, purity = 94%; Factor XIa Ki = 170 nM, plasma kallikrein Ki = 5,700 nM.

Example 262

(9R,13S)-13-(4-{3-chloro-6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluorophenyl}-6-oxo-1 ,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), Preparation of 4,14,16-pentaen-8-one

262A. Preparation of 6-(3-chloro-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorophenyl)pyrimidin-4-ol

6-(3-chloro-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-fluorophenyl)pyrimidin-4-ol (0.032 g, 85% yield) 4-(2-bromo-5-chlorophenyl)-6-methoxypyrimidine (0.08 g, 0.267 mmol) was reacted with 4-(6-bromo-3-) in a manner similar to the procedure described in Examples 140A and 140B. It was prepared by replacing with chloro-2-fluorophenyl)-6-methoxypyrimidine (0.1 g, 0.315 mmol). MS(ESI) m/z: 341.4 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.35 (s, 1H), 8.06 (s, 1H), 7.67 - 7.60 (m, 2H), 7.45 (t, J=59.4 Hz, 1H), 7.40 (dd, J=8.3, 1.4 Hz, 1H), 6.52 (s, 1H).

262B. (9R,13S)-13-(4-{3-chloro-6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluorophenyl}-6-oxo-1 ,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), 4,14,16-pentaen-8-one trifluoroacetate production

(9R,13S)-13-(4-{3-chloro-6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluorophenyl}-6-oxo-1 ,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), 4,14,16-pentaen-8-one trifluoroacetate (11.7 mg, 36% yield) was purified from 6-{5-chloro-2-[4-( Trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (22.8 mg, 0.067 mmol) was reacted with 6-(3-chloro-6-(1-( It was prepared by replacing difluoromethyl)-1H-pyrazol-4-yl)-2-fluorophenyl)pyrimidin-4-ol (14.79 mg, 0.043 mmol). MS(ESI) m/z: 623.6 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.99 (s, 1H), 8.75 (d, J=5.2 Hz, 1H), 8.00 (s, 1H), 7.73 (s, 1H), 7.64 - 7.58 (m, 2H), 7.55 - 7.28 (m, 4H), 6.51 (s, 1H), 6.04 (dd, J=12.7, 3.9 Hz, 1H), 4.05 (s, 3H), 2.75 - 2.67 (m, 1H), 2.36 (tt, J=12.7, 4.3 Hz, 1H), 2.13 - 2.02 (m, 2H), 1.66 - 1.45 (m, 2H), 1.02 (d, J=7.2 Hz, 3H), 0.83 - 0.66 (m, 1H) ). ¹⁹ F NMR (471 MHz, CD ₃ OD) δ -77.75 (s), -96.25 (s), -117.96 (s). Analytical HPLC (Method A): RT = 8.18 min, 98.0% purity; Factor XIa Ki = 4.5 nM, plasma kallikrein Ki = 340 nM.

Example 263

(9R,13S)-13-[4-(5-chloro-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl )-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- manufacture of onion

263A. Preparation of 6-(5-chloro-1H-indol-7-yl)pyrimidin-4-ol

6-(5-Chloro-1H-indol-7-yl)pyrimidin-4-ol was reacted with 4-bromo-6-chloro-1H-benzo[d]imidazole in a manner similar to that described in Example 207C. -Prepared by replacing with bromo-5-chloro-1H-indole. MS(ESI) m/z: 246 (M+H) ⁺ .

263B. (9R,13S)-13-[4-(5-chloro-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl )-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- Ontrifluoroacetate

(9R,13S)-13-[4-(5-chloro-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoromethyl )-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- Ontrifluoroacetate was reacted with 6-(5-chloro-1H-indol-7-yl)pyrimidin-4-ol in a similar manner as described in Example 56 and (9R,13S) prepared as described in Intermediate 30. -13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15 tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6), Prepared using 4,14,16-pentaen-8-one (0.61 mg, 1.3%). MS(ESI) m/z: 564 (M+H) ⁺ and 566 (M+2+H) ⁺ . Analytical HPLC (Method A): RT = 9.71 min, purity = >90%; Factor XIa Ki = 4,600 nM.

Example 264

(9R,13S)-13-[4-(6-chloro-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoro Methyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8 -manufacture of

264A. Preparation of 6-(6-chloro-1H-indazol-4-yl)pyrimidin-4-ol

6-(6-Chloro-1H-indazol-4-yl)pyrimidin-4-ol was reacted with 4-bromo-6-chloro-1H-benzo[d]imidazole in a manner similar to that described in Example 207C. It was prepared by replacing it with 4-bromo-6-chloro-1H-indazole. MS(ESI) m/z: 247 (M+H) ⁺ .

264B. (9R,13S)-13-[4-(6-chloro-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoro methyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaene-8 -Manufacture of ontrifluoroacetate

(9R,13S)-13-[4-(6-chloro-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-(difluoro Methyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8 -one trifluoroacetate (4 mg, 9.4%) was reacted with 6-(6-chloro-1H-indazol-4-yl)pyrimidin-4-ol in a manner similar to Example 56 and as described in Intermediate 30. Prepared (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1( It was prepared using 18),2(6),4,14,16-pentaen-8-one. MS(ESI) m/z: 565 (M+H) ⁺ .

^1H NMR (400MHz, DMSO-d ₆ ) d 9.35 (s, 1H), 9.05 (s, 1H), 8.69 (d, J=5.3 Hz, 1H), 8.53 (s, 1H), 7.90 - 7.84 (m , 2H), 7.75 - 7.68 (m, 4H), 7.40 - 7.35 (m, 2H), 7.02 (s, 1H), 2.62 - 2.58 (m, 1H), 2.36 - 2.30 (m, 1H), 2.06 - 2.01 (m, 1H), 1.93 - 1.87 (m, 1H), 1.47 - 1.42 (m, 1H), 1.34 - 1.29 (m, 1H), 0.83 (d, J=6.8 Hz, 3H). Analytical HPLC (Method A): RT = 7.32 min, purity = 95%; Factor XIa Ki = 260 nM.

Example 265

(14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1, 6-dihydropyrimidin-1-yl)-10-methyl-5,8,16-triazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2(7),3,5 Preparation of 15,17-hexaen-9-one trifluoroacetate

265A. Preparation of (S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronic acid, trifluoroacetate

5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (1.198 g, 5.30) prepared as described in Intermediate 23 in DMSO (10 mL) mmol) and (S)-tert-butyl (1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (1.0 g, 3.54 mmol) under Ar under KOAc ( 1.041 g, 10.61 mmol) was added. PdCl ₂ (dppf)·CH ₂ Cl ₂ adduct (0.289 g, 0.354 mmol) and the mixture were purged with Ar for an additional 10 minutes and then stirred at 85°C. After 12 hours, the reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The dark oil was purified by reverse phase chromatography, concentrated and lyophilized, and then (S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4- Mono)boronic acid trifluoroacetate (1.05 g, 2.59 mmol, 73.1% yield) was obtained as a white solid. MS(ESI) m/z: 293.2 (M+H) ⁺ .

265B. Preparation of (S)-tert-butyl (1-(3'-amino-[4,4'-bipyridin]-2-yl)but-3-en-1-yl) carbamate.

(S)-(2-(1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)pyridin-4-yl)boronic acid in dioxane (17 mL), trifluoro To a solution of acetate (1.0 g, 2.462 mmol) and 4-bromopyridin-3-amine (0.511 g, 2.95 mmol) was added 2 M aqueous Na ₂ CO ₃ (4.92 mL, 9.85 mmol). The mixture was purged with a stream of Ar for 5 minutes. Pd(PPh ₃ ) ₄ (0.285 g, 0.246 mmol) was added, and the reaction was irradiated at 120°C for 1 hour. The reaction was quenched with water (40 mL) and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated. The crude material was purified by normal phase column chromatography eluting with a gradient of DCM/MeOH to give (S)-tert-butyl (1-(3'-amino-[4,4'-bipyridin]-2-yl)butyl. -3-en-1-yl)carbamate (0.736 g, 88% yield) was obtained as a brown oil. MS(ESI) m/z: 341.2 (M+H) ⁺ .

^1H NMR (500MHz, CDCl ₃ ) δ 8.68 (d, J=4.7 Hz, 1H), 8.19 (s, 1H), 8.10 (d, J=5.0 Hz, 1H), 7.35 (s, 1H), 7.29 ( dd, J=5.1, 1.5 Hz, 1H), 7.02 (d, J=5.0 Hz, 1H), 5.79 - 5.68 (m, 1H), 5.62 - 5.52 (m, 1H), 5.11 - 5.04 (m, 2H) , 4.90 - 4.80 (m, 1H), 3.83 (br. s., 2H), 2.64 (t, J=6.7 Hz, 2H), 1.45 (s, 9H).

265C. tert-Butyl ((S)-1-(3'-((R)-2-methylbut-3-enamido)-[4,4'-bipyridin]-2-yl)but-3-ene -1-day) Preparation of carbamate

(S)-tert-butyl (1-(3'-amino-[4,4'-bipyridin]-2-yl)but-3-en-1-yl) carbamate ( (R)-2-methylbut-3-enoic acid (303 mg, 3.03 mmol) was added to a solution of 736 mg, 2.16 mmol). After cooling to 0°C, pyridine (0.525 mL, 6.49 mmol) was added followed by T3P®/50% EtOAc (2.57 mL, 4.32 mmol) dropwise. The reaction was slowly warmed to room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated. The crude material was purified by normal phase column chromatography eluting with a gradient of DCM/MeOH to give tert-butyl ((S)-1-(3'-((R)-2-methylbut-3-enamido)- [4,4'-bipyridin]-2-yl)but-3-en-1-yl)carbamate (815 mg, 89%) was obtained. MS(ESI) m/z: 423.2 (M+H) ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.45 (s, 1H), 8.70 (d, J=5.0 Hz, 1H), 8.49 (d, J=5.0 Hz, 1H), 7.24 (br. s., 1H) , 7.21 (s, 1H), 7.18 - 7.14 (m, 2H), 5.80 (ddd, J=17.1, 10.1, 8.3 Hz, 1H), 5.74 - 5.66 (m, 1H), 5.54 - 5.48 (m, 1H) , 5.15 - 5.05 (m, 4H), 4.92 - 4.85 (m, 1H), 3.08 (quin, J=7.2 Hz, 1H), 2.69 - 2.61 (m, 2H), 1.45 (s, 9H), 1.31 - 1.28 (m, 3H).

265D. tert-Butyl N-[(11E,14S)-10-methyl-9-oxo-5,8,16-triazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7) ,3,5,11,15,17-heptaen-14-yl]Manufacture of carbamate

tert-Butyl((S)-1-(3'-((R)-2-methylbut-3-enamido)-[4,4'-bipyridine in freshly opened and degassed DCM (500 mL) To a solution of ]-2-yl)but-3-en-1-yl)carbamate (400 mg, 0.947 mmol) was added p-TsOH·H ₂ O (378 mg, 1.988 mmol). A stream of N ₂ was bubbled for 10 minutes and then the solution was heated at 40° C. under a nitrogen atmosphere. After 1 hour, second generation Grubbs catalyst (201 mg, 0.237 mmol) dissolved in degassed DCM (20 ml) was added dropwise to the reaction mixture and heating was continued at 40° C. overnight. The reaction mixture was quenched with 1.5 MK ₂ HPO ₃ (30 mL) and the organic phase was then separated and concentrated. The crude residue was purified by reverse phase chromatography and the product fractions were concentrated. The residue was dissolved in MeOH, neutralized by passing through NaHCO ₃ resin cartridges (2x), and the filtrate was concentrated to give tert-butyl N-[(11E,14S)-10-methyl-9-oxo-5,8, 16-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (24.6 mg , 6.59% yield) was obtained as a brown film. MS(ESI) m/z: 395 (M+H) ⁺ .

265E. tert-Butyl N-[(14S)-10-methyl-9-oxo-5,8,16-triazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3 , 5,15,17-hexaen-14-yl] Preparation of carbamate

PtO ₂ (0.018 g, 0.079 mmol) was dissolved in tert-butyl N-[(11E,14S)-10-methyl-9-oxo-5,8,16-triazatricyclo[13.3.1.0) in EtOH (3 mL). ^2,7 ]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.031 g, 0.079 mmol) was added to a stirred solution , and treated with H ₂ atmosphere (55 psi) for 3 hours. The catalyst was filtered through a plug of Celite® and the filtrate was concentrated to give tert-butyl N-[(14S)-10-methyl-9-oxo-5,8,16-triazatricyclo[13.3.1.0 ^{2 ,7} ]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate was obtained as a brown film (yield was estimated quantitatively). MS(ESI) m/z: 397 (M+H) ⁺ .

265F. (14S)-14-amino-10-methyl-5,8,16-triazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2(7),3,5,15,17 -Preparation of hexaen-9-one

TFA (0.18 mL, 2.35 mmol) was dissolved in tert-butyl N-[(14S)-10-methyl-9-oxo-5,8,16-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1( 19),2(7),3,5,15,17-hexaen-14-yl]carbamate (31 mg, 0.078 mmol) was added to the stirring solution. After 6 hours, the reaction mixture was concentrated and the residue was placed under vacuum overnight. The residue was dissolved in MeOH, passed through a NaHCO ₃ resin cartridge and concentrated to give (14S)-14-amino-10-methyl-5,8,16-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca. -1(19),2(7),3,5,15,17-hexaen-9-one was obtained as a brown film. The material was carried over to subsequent reactions without further purification. MS(ESI) m/z: 297.3 (M+H) ⁺ .

265G. (14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1, 6-dihydropyrimidin-1-yl)-10-methyl-5,8,16-triazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2(7),3,5 , 15,17-hexaen-9-one trifluoroacetate production

(14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1, 6-dihydropyrimidin-1-yl)-10-methyl-5,8,16-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5 , 15,17-hexaen-9-one, trifluoroacetate was reacted with (14S)-14-amino-10-methyl-5,8,16-triazatricyclo [13.3.1.0 in a manner similar to Example 56. ^2,7 ]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one and 6-{5-chloro-2-[ prepared as described in Intermediate 15 Prepared using 4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (10.4 mg, 16.5%). The compound exists as an apparent diastereomeric mixture according to NMR data. MS(ESI) m/z: 621.2 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.88 - 8.81 (m, 4H), 8.75 - 8.69 (m, 3H), 8.07 (br. s., 1H), 8.03 (br. s., 1H), 7.96 (d, J=2.2 Hz, 1H), 7.95 - 7.93 (m, 1H), 7.84 - 7.82 (m, 1H), 7.80 - 7.79 (m, 1H), 7.76 - 7.73 (m, 2H), 7.59 (dd , J=5.0, 1.7 Hz, 1H), 7.47 (dd, J=5.1, 1.8 Hz, 1H), 7.27 (s, 1H), 6.49 - 6.45 (m, 2H), 6.09 (dd, J=12.4, 4.7 Hz, 1H), 5.94 - 5.83 (m, 2H), 4.61 (dd, J=15.2, 9.7 Hz, 1H), 2.94 - 2.86 (m, 1H), 2.79 - 2.70 (m, 1H), 2.26 (s, 1H), 2.03 (d, J=13.0 Hz, 1H), 1.35 - 1.28 (m, 1H), 1.15 (d, J=6.6 Hz, 3H), 1.00 (d, J=6.8 Hz, 2H). Analytical HPLC (Method A): RT = 5.22 min, purity = 98%.

Example 267

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-9-methyl-4-(6-oxo-1,6-dihydropyridazin-4-yl)-3,4,7,15-tetraazatri Preparation of cyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-9-methyl-4-(6-oxo-1,6-dihydropyridazin-4-yl)-3,4,7,15-tetraazatri Cyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one trifluoroacetate (2.8 mg, 10% yield) was prepared by the procedure described in Example 216. 5-iodopyridazin-3(2H)-one (7.28 mg, 0.033 mmol) and (9R,13S)-13-(4-{5-chloro-) prepared in a similar manner as described in Example 196. 2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9- Methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (20.0 mg , 0.033 mmol).

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.64 (s, 1H), 9.21 (s, 1H), 8.80 (s, 1H), 8.70 (s, 1H), 8.65 (d, J=2.4 Hz, 1H ), 8.59 (d, J=4.9 Hz, 1H), 7.96 (d, J=1.8 Hz, 1H), 7.89 (s, 1H), 7.86 - 7.76 (m, 2H), 7.63 (d, J=5.2 Hz) , 1H), 7.30 - 7.00 (m, 1H), 6.48 (s, 1H), 6.00 (br. s., 1H), 2.78 (br. s., 1H), 2.24 (d, J=16.2 Hz, 2H ), 1.91 - 1.76 (m, 1H), 1.55 (br. s., 1H), 1.40 (br. s., 1H), 0.92 (d, J=6.7 Hz, 3H), 0.48 (br. s., 1H). MS(ESI) m/z: 704.0 [M+H] ⁺ . Analytical HPLC (Method B): RT = 1.735 min, purity = 98.0%; Factor XIa Ki = 0.21 nM, plasma kallikrein Ki = 9 nM.

Example 268

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyrazin-2-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ] Preparation of octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyrazin-2-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2,5,14,16-pentaen-8-one trifluoroacetate (10.9 mg, 16% yield) was reacted with 2-io in a manner similar to the procedure described in Example 216. Do-6-methoxypyrazine (19.35 mg, 0.082 mmol) and (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl) prepared as described in Example 196 )-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15- It was prepared using tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (50.0 mg, 0.082 mmol).

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.54 (s, 1H), 9.19 (s, 1H), 8.78 (s, 1H), 8.73 (s, 1H), 8.66 (s, 1H), 8.56 (d) , J=4.9 Hz, 1H), 8.28 (s, 1H), 7.96 - 7.88 (m, 1H), 7.84 - 7.75 (m, 2H), 7.61 (d, J=4.6 Hz, 1H), 7.21 - 6.93 ( m, 1H), 6.46 (s, 1H), 6.00 (br. s., 1H), 4.01 (s, 3H), 2.75 (br. s., 1H), 2.31 - 2.14 (m, 2H), 1.85 - 1.73 (m, 1H), 1.53 (br. s., 1H), 1.37 (br. s., 1H), 0.90 (d, J=6.7 Hz, 3H), 0.52 (br. s., 1H). MS(ESI) m/z: 718.0 [M+H] ⁺ . Analytical HPLC (Method B): RT = 2.06 min, purity = 100.0%; Factor XIa Ki = 9 nM, plasma kallikrein Ki = 260 nM.

Example 269

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-methoxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[ 12.3.1.0 Preparation of ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-methoxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[ 12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one (6.6 mg, 19%) was reacted with 5-fluorophenol in a manner similar to the procedure described in Example 216. Ro-4-iodo-2-methoxypyridine (21 mg, 0.082 mmol) and (9R,13S)-13-(4-{5-chloro-2-[4-) prepared as described in Example 196 (trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4 ,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.025 g, 0.041 mmol) It was manufactured using. MS(ESI) m/z: 735.4 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.60 (s, 1H), 9.23 (s, 1H), 8.72 (s, 1H), 8.60 (d, J=5.2 Hz, 1H), 8.49 (d, J =1.8 Hz, 1H), 8.43 (d, J=3.1 Hz, 1H), 7.98 (d, J=2.1 Hz, 1H), 7.92 (s, 1H), 7.90 - 7.80 (m, 2H), 7.64 (d , J=4.9 Hz, 1H), 7.39 (d, J=5.5 Hz, 1H), 6.51 (s, 1H), 6.12 - 5.90 (m, 1H), 3.93 (s, 3H), 2.79 (br. s. , 1H), 2.27 (d, J=17.7 Hz, 2H), 1.84 (br. s., 1H), 1.57 (br. s., 1H), 1.49 - 1.34 (m, 1H), 0.94 (d, J =6.7 Hz, 3H), 0.68 - 0.41 (m, 1H). Analytical HPLC (Method C): RT = 2.09 min, purity = 100%; Factor XIa Ki = 7.4 nM, plasma kallikrein Ki = 280 nM.

Example 270

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,14,16-pentaene-17-carbonitrile

270A. tert-Butyl N-[(9R,10E,13S)-17-cyano-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl] Preparation of carbamate

tert-Butyl N-[(9R,10E,13S)-17-cyano-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (0.02 g, 45%), a dark film was prepared as described in Intermediate 35D. It was prepared by replacing 3-bromobenzaldehyde with 2-bromo-4-formylbenzonitrile in the same manner as described above. LCMS (ESI) m/z: 458.6 (M+H) ⁺ .

270B. tert-Butyl N-[(9R,13S)-17-cyano-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^{2, 6} ] Preparation of octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

tert-Butyl N-[(9R,10E,13S)-17-cyano-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triaza in EtOH (10 ml) PtO in tricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate (20 mg, 0.044 mmol) ₂ (0.005 g, 0.022 mmol) was added and the reaction was hydrogenated at 55 psi for 5 hours. The reaction mixture was filtered through a plug of Celite® and the filtrate was concentrated. To the product was added DCM (2 ml), TEA (6.09 μl, 0.044 mmol) and Des-Martin periodinane (74.2 mg, 0.175 mmol). After 1 hour at room temperature, the reaction was quenched with saturated aqueous Na ₂ S ₂ O ₃ and extracted with EtOAc (2 x 15 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO ₄ ), filtered and concentrated to give tert-butyl N-[(9R,13S)-17-cyano-3-(difluoromethyl). -9- Methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-13 -yl]carbamate (20 mg 100%) was obtained. MS(ESI) m/z: 460.5 (M+H) ⁺ .

270C. (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( Preparation of 18),2(6),4,14,16-pentaene-17-carbonitrile

tert-Butyl N-[(9R,13S)-17-cyano-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate (20 mg, 0.044 mmol) in dioxane (1 ml) followed by dioxane 1 ml of 4 N HCl was added. After 3 hours, the reaction was concentrated and the residue was dissolved in DCM/MeOH and filtered through a basic cartridge. The filtrate was concentrated to (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ] Octadeca-1(18),2(6),4,14,16-pentaene-17-carbonitrile (12 mg, 80%) was obtained as a brown solid. MS(ESI) m/z: 360.4 (M+H) ⁺ .

270D. (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,14,16-pentaene-17-carbonitrile

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo [12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,14,16-pentaene-17-carbonitrile (2.2 mg, 9.6%) was reacted with (9R,13S)-13- in a manner similar to that described in Example 56. Amino-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6), Prepared using 4,14,16-pentaene-17-carbonitrile. MS(ESI) m/z: 683.9 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.71 (s, 1H), 8.13 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.80 (m, 2H), 7.68 - 7.61 (m, 3H), 7.58 - 7.51 (m, 2H), 6.34 (s, 1H), 5.62 (d, J=12.9 Hz, 1H), 2.45 - 2.34 (m, 1H), 2.22 (br. s., 1H), 2.00 (d, J=16.2 Hz, 1H), 1.64 (d, J=10.2 Hz, 2H), 1.44 (d, J=7.2 Hz, 1H), 1.06 (d, J=6.6 Hz, 3H), 0.62 ( br. s., 1H). Analytical HPLC (Method C) RT = 1.93 min, purity = 100% as a mixture of diastereomers; Factor XIa Ki = 0.35 nM, plasma kallikrein Ki = 84 nM.

Example 271

(9R,13S)-13-{4-[5-chloro-2-(4-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene Preparation of -8-one

(9R,13S)-13-{4-[5-chloro-2-(4-methyl-1H-imidazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene -8-one trifluoroacetate (11.7 mg, 45% yield) was obtained from (9R,13S)-13-{4-[5-chloro-2-(5-methyl-1H-imidazol-1-yl)phenyl ]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18),2(6),4,14,16-pentaen-8-one trifluoroacetate, was the main product isolated from the preparation of Example 257. MS(ESI) m/z: 569.20 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.23 (s, 1H), 9.14 (br. s., 1H), 8.77 (s, 1H), 8.68 (d, J=4.9 Hz, 1H), 7.94 ( d, J=2.1 Hz, 1H), 7.85 (dd, J=8.4, 2.3 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.59 (d, J=5.2 Hz, 1H), 7.52 - 7.47 (m, 2H), 6.60 (s, 1H), 5.90 (d, J=9.8 Hz, 1H), 4.01 (s, 3H), 2.69 - 2.61 (m, 1H), 2.35 - 2.24 (m, 4H), 2.16 - 2.06 (m, 1H), 1.88 - 1.78 (m, 1H), 1.52 - 1.42 (m, 1H), 1.38 - 1.28 (m, 1H), 0.89 (d, J= 7.0 Hz, 3H), 0.53 - 0.38 (m, 1H). Analytical HPLC (Method C): RT = 1.14 min, 100% purity; Factor XIa Ki = 90 nM, plasma kallikrein Ki = 4,600 nM.

Example 272

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-hydroxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[ 12.3.1.0 Preparation of ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1- prepared as described in Example 269 yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-methoxypyridin-4-yl)-9-methyl-3,4, 7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one (0.02 g, 0.027 mmol) was dissolved in THF (2 mL). ), concentrated HCl (500 μl, 6.00 mmol) was added, and the reaction mixture was heated to 70° C. for 16 hours. Afterwards, the solvent was concentrated, and the residue was purified by reverse phase chromatography to obtain (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1, 2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(5-fluoro-2-hydroxypyridin-4-yl) -9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one (5.3 mg , 26%) was obtained. MS(ESI) m/z: 721.2 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.59 (s, 1H), 9.24 (s, 1H), 8.73 (s, 1H), 8.60 (d, J=4.9 Hz, 1H), 8.43 (s, 1H) ), 8.05 (br. s., 1H), 7.98 (d, J=1.8 Hz, 1H), 7.92 (s, 1H), 7.90 - 7.79 (m, 2H), 7.63 (d, J=4.0 Hz, 1H) ), 6.96 (br. s., 1H), 6.51 (s, 1H), 6.14 - 5.94 (m, 1H), 2.79 (br. s., 1H), 2.27 (d, J=17.1 Hz, 2H), 1.91 - 1.77 (m, 1H), 1.64 - 1.50 (m, 1H), 1.49 - 1.34 (m, 1H), 0.94 (d, J=6.7 Hz, 3H), 0.64 - 0.42 (m, 1H). Analytical HPLC (Method C): RT = 1.68 min, purity = 100%; Factor XIa Ki = 0.73 nM, plasma kallikrein Ki = 130 nM.

Example 274

(9R,13S)-13-{4-[5-chloro-2-(1,3-oxazol-2-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl} -3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8 -manufacture of

(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]- prepared as described in Example 211 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaene-8- To a solution of (20 mg, 0.033 mmol) in degassed dioxane (1 ml) was added 2-(tributylstannyl)oxazole (11.65 mg, 0.033 mmol), followed by Pd(Ph ₃ P) ₄ (3.76 mg, 3.25 μmol) was added. The reaction was stirred at 90° C. for 2 hours, then cooled to room temperature and concentrated. Purified by reverse phase chromatography to give (9R,13S)-13-{4-[5-chloro-2-(1,3-oxazol-2-yl)phenyl]-6-oxo-1,6-dihydro. Pyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14 ,16-pentaen-8-one trifluoroacetate (2.38 mg, 11% yield) was obtained as a white solid. MS(ESI) m/z: 556.4 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.89 (s, 1H), 8.74 (d, J=5.1 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 7.71 (s, 1H), 7.69 (d, J=2.2 Hz, 1H), 7.65 (dd, J=8.4, 2.2 Hz, 1H), 7.52 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 7.23 (s, 1H), 6.50 (s, 1H), 6.05 (dd, J=12.7, 4.1 Hz, 1H), 4.05 (s, 3H), 2.77 - 2.67 (m, 1H), 2.38 - 2.27 (m, 1H), 2.15 - 1.98 (m, 2H), 1.68 - 1.42 (m, 2H), 1.01 (d, J=7.0 Hz, 3H), 0.77 - 0.62 (m, 1H). Analytical HPLC (Method A): RT = 7.13 min, 99.0% purity; Factor XIa Ki = 100 nM, plasma kallikrein Ki = 4,500 nM.

Example 275

(9R,13S)-13-(4-{5-chloro-2-[(pyrazin-2-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3 ,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one manufacture of

(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3 prepared as described in Example 313 ,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-8-one A sealed microwave vial containing hydrochloride (0.01 g, 0.017 mmol), 2-bromopyrazine (5.51 mg, 0.035 mmol) and EtOH (1 ml) was heated in the microwave at 150°C for 30 min and incubated at room temperature. Cooled and concentrated. The residue contained Cs ₂ CO ₃ (0.030 g, 0.093 mmol), Pd(OAc) ₂ (1.05 mg, 4.66 μmol), Xantphos (5.39 mg, 9.31 μmol), and 2-bromopyrazine (5.51 mg, 0.035 mmol). Then dioxane (0.931 ml) was added. The reaction mixture was degassed with Ar for 10 minutes. The vial was sealed and heated at 85°C. After 4 hours, the reaction was cooled to room temperature and concentrated. Purified by reverse phase chromatography, (9R,13S)-13-(4-{5-chloro-2-[(pyrazin-2-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidine -1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16 -Pentaen-8-one trifluoroacetate (2.95 mg, 20% yield) was obtained as a yellow solid. MS(ESI) m/z: 582.5 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.09 (s, 1H), 8.73 (d, J=5.1 Hz, 1H), 8.23 - 8.19 (m, 2H), 8.08 (dd, J=2.8, 1.4 Hz, 1H), 7.89 (d, J=2.6 Hz, 1H), 7.73 (s, 1H), 7.67 (d, J=2.6 Hz, 1H), 7.53 (dd, J=5.1, 1.5 Hz, 1H), 7.50 ( s, 1H), 7.43 (dd, J=8.9, 2.5 Hz, 1H), 6.77 (s, 1H), 6.02 (dd, J=12.7, 4.3 Hz, 1H), 4.05 (s, 3H), 2.76 - 2.67 (m, 1H), 2.43 - 2.32 (m, 1H), 2.15 - 2.01 (m, 2H), 1.68 - 1.44 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.81 - 0.65 (m , 1H). Analytical HPLC (Method A): RT = 7.06 min, 94.0% purity; Factor XIa Ki = 560 nM.

Example 276

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(4-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]Preparation of octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(4-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]Octadeca-1(18),2,5,14,16-pentaen-8-one trifluoroacetate was prepared in a manner similar to the procedure described in Example 296 to give (9R,13S)-13- (4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidine -1-yl)-4-(4-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( 18), 2,5,14,16-pentaen-8-one trifluoroacetate (3.82 mg, 4.44 μmol, 42% yield) was obtained.

^1H NMR (400MHz, CD ₃ OD) δ 8.85 (s, 1H), 8.75 (s, 2H), 8.71 (s, 1H), 8.67 - 8.62 (m, 1H), 8.27 (s, 1H), 8.00 - 7.93 (m, 2H), 7.82 - 7.69 (m, 3H), 6.49 (s, 1H), 6.13 (d, J=9.2 Hz, 1H), 2.87 (br. s., 1H), 2.29 (br. s. ., 2H), 2.13 - 2.01 (m, 1H), 1.76 (d, J=10.3 Hz, 1H), 1.59 (br. s., 1H), 1.29 (s, 1H), 1.11 (d, J=7.0 Hz, 3H), 0.91 (br. s., 1H). MS(ESI) m/z: 704.5 [M+H] ⁺ . Analytical HPLC (Method A): RT = 7.04 min, purity = >95.0%; Factor XIa Ki = 2.4 nM, plasma kallikrein Ki = 70 nM.

Example 277

Ethyl 1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-3-methyl -Preparation of 1H-pyrazole-4-carboxylate

Ethyl 3-methyl-1H-pyrazole-4-carboxylate (3.51 mg, 0.023 mmol), K ₃ PO ₄ (9.79 mg, 0.046 mmol) and (9R,13S)-13- in dioxane (0.24 mL). [4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatri (1R,2R)- in a suspension of cyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (14 mg, 0.023 mmol) N1,N2-dimethylcyclohexane-1,2-diamine (1.619 mg, 0.011 mmol) was added. The mixture was purged with Ar, CuI (0.434 mg, 2.277 μmol) was added and the vial was sealed. The reaction was heated at 80° C. and stirred overnight. The solution was concentrated and the residue was purified by reverse phase chromatography to give ethyl 1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7 ,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6- Dihydropyrimidin-4-yl}phenyl)-3-methyl-1H-pyrazole-4-carboxylate trifluoroacetate (3.21 mg, 17% yield) was obtained as a white solid. MS(ESI) m/z: 641.2 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.86 (s, 1H), 8.71 (d, J=5.1 Hz, 1H), 8.20 (s, 1H), 7.84 (d, J=2.2 Hz, 1H), 7.68 (s, 1H), 7.67 - 7.61 (m, 1H), 7.60 - 7.54 (m, 1H), 7.53 - 7.47 (m, 2H), 6.20 (s, 1H), 6.02 - 5.95 (m, 1H), 4.30 - 4.21 (m, 2H), 4.07 - 4.01 (m, 3H), 2.70 (td, J=6.7, 3.2 Hz, 1H), 2.36 (s, 3H), 2.33 - 2.24 (m, 1H), 2.13 - 1.95 (m, 2H), 1.65 - 1.53 (m, 1H), 1.51 - 1.40 (m, 1H), 1.34 - 1.26 (m, 3H), 1.00 (d, J=7.0 Hz, 3H), 0.69 (m, 1H) ). Analytical HPLC (Method A): RT =7.46 min, 94% pure; Factor XIa Ki = 170 nM, plasma kallikrein Ki = 2,700 nM.

Example 278

(9R,13S)-13-{4-[5-chloro-2-(3,4-dimethyl-1H-pyrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidine- 1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16- Preparation of pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(3,4-dimethyl-1H-pyrazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidine- 1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16- Pentaen-8-one trifluoroacetate (0.85 mg, 5% yield) was reacted with ethyl 3-methyl-1H-pyrazole-4-carboxylate to 3,4-dimethyl in a manner similar to the procedure described in Example 277. It was prepared by replacing -1H-pyrazole (2.189 mg, 0.023 mmol). MS(ESI) m/z: 583.2 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.91 (s, 1H), 8.72 (d, J=5.1 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.68 (s, 1H), 7.60 (dd, J=8.6, 2.4 Hz, 1H), 7.51 (dd, J=5.1, 1.5 Hz, 1H), 7.49 - 7.46 (m, 2H), 7.39 (s, 1H), 6.02 - 5.94 (m, 2H) ), 4.04 (s, 3H), 2.71 (d, J=3.1 Hz, 1H), 2.37 - 2.24 (m, 1H), 2.14 (s, 3H), 2.00 (s, 3H), 1.93 (s, 1H) , 1.66 - 1.54 (m, 1H), 1.48 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.68 (m, 1H). Analytical HPLC (Method A): RT = 6.78 min, 92% purity; Factor XIa Ki = 540 nM.

Example 279

Ethyl 1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyra Preparation of sol-4-carboxylate

Ethyl 1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-pyra Sol-4-carboxylate trifluoroacetate (9.9 mg, 56% yield) was purified from ethyl 3-methyl-1H-pyrazole-4-carboxylate in a manner similar to the procedure described in Example 277. Prepared by replacing with sol-4-carboxylate (3.19 mg, 0.023 mmol). MS(ESI) m/z: 627.1 (M+H) ⁺ .

^1H NMR (400MHz, methanol-d4) δ 8.86 (s, 1H), 8.72 (d, J=5.3 Hz, 1H), 8.34 (s, 1H), 7.96 (s, 1H), 7.85 (d, J= 2.2 Hz, 1H), 7.69 (s, 1H), 7.68 - 7.64 (m, 1H), 7.61 - 7.57 (m, 1H), 7.53 (dd, J=5.2, 1.7 Hz, 1H), 7.49 (s, 1H) ), 6.18 (s, 1H), 5.98 (dd, J=12.7, 4.3 Hz, 1H), 4.28 (q, J=7.1 Hz, 2H), 4.04 (s, 3H), 2.70 (td, J=6.7, 3.3 Hz, 1H), 2.30 (tt, J=12.7, 4.4 Hz, 1H), 2.12 - 1.94 (m, 2H), 1.66 - 1.53 (m, 1H), 1.46 (ddd, J=15.0, 9.8, 5.5 Hz) , 1H), 1.32 (t, J=7.2 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H), 0.69 (m, 1H). Analytical HPLC (Method A): RT = 7.06 min, 99% purity; Factor XIa Ki = 2.2 nM, plasma kallikrein Ki = 960 nM.

Example 280

(9R,13S)-13-[4-(5-chloro-2-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4 Preparation of 7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

A mixture of 1H-imidazole (2.21 mg, 0.033 mmol), Pd(OAc) ₂ (0.73 mg, 3.25 μmol) and CuI (0.012 g, 0.065 mmol) in DMF (1.63 ml) was purged with Ar (3x). , (9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl] prepared as described in Example 211. -3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8 -one (0.02 g, 0.033 mmol) was added. The reaction was sealed and heated at 140°C. After 5 hours, the reaction was cooled to room temperature. The solution was concentrated and the residue was purified by reverse phase chromatography to obtain (9R,13S)-13-[4-(5-chloro-2-hydroxyphenyl)-6-oxo-1,6-dihydropyrimidine. -1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16 -Pentaen-8-one trifluoroacetate (1.76 mg, 9% yield) was obtained as a yellow solid. MS(ESI) m/z: 505.6 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.11 (s, 1H), 8.74 (d, J=5.1 Hz, 1H), 7.84 (d, J=2.6 Hz, 1H), 7.72 (s, 1H), 7.52 (dd, J=5.1, 1.5 Hz, 1H), 7.50 (s, 1H), 7.30 (dd, J=8.8, 2.6 Hz, 1H), 7.07 (s, 1H), 6.90 (d, J=8.8 Hz, 1H), 6.06 (dd, J=12.9, 4.5 Hz, 1H), 4.05 (s, 3H), 2.78 - 2.68 (m, 1H), 2.35 (tt, J=12.8, 4.3 Hz, 1H), 2.16 - 2.01 (m, 2H), 1.68 - 1.45 (m, 2H), 1.01 (d, J=7.0 Hz, 3H), 0.76 - 0.61 (m, 1H). Analytical HPLC (Method A): RT = 8.47 min, 100% purity; Factor XIa Ki = 57 nM, plasma kallikrein Ki = 180 nM.

Example 281

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}-6-oxo-1,6-dihydro Pyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14 , Preparation of 16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}-6-oxo-1,6-dihydro Pyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14 , 16-pentaen-8-one trifluoroacetate (4 mg, 15% yield) was reacted with 4-(trifluoromethyl)-1H-imidazole in a manner similar to the procedure described in Example 231. It was prepared by replacing with (0.018 g, 0.130 mmol). MS(ESI) m/z: 623.25 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.84 (s, 1H), 8.70 (d, J=5.2 Hz, 1H), 7.86 (s, 1H), 7.83 (d, J=2.5 Hz, 1H), 7.74 (s, 1H), 7.71 - 7.66 (m, 2H), 7.58 (d, J=8.5 Hz, 1H), 7.52 - 7.47 (m, 2H), 6.40 (s, 1H), 5.99 (dd, J=12.5) , 3.4 Hz, 1H), 4.04 (s, 3H), 2.70 (dt, J=6.6, 3.3 Hz, 1H), 2.33 - 2.23 (m, 1H), 2.12 - 1.92 (m, 2H), 1.65 - 1.55 ( m, 1H), 1.52 - 1.41 (m, 1H), 1.01 (d, J=6.9 Hz, 3H), 0.76 - 0.60 (m, 1H). Analytical HPLC (Method C): RT = 1.58 min, 100% purity; Factor XIa Ki = 73 nM, plasma kallikrein Ki = 4,700 nM.

Example 282

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-4-methanesulfonyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5 , Preparation of 14,16-pentaen-8-one, and

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3-methanesulfonyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), Preparation of 4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]- prepared as described in Example 101 6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18), Cooled (0° C.), clear, light pink solution of 2(6),4,14,16-pentaen-8-one trifluoroacetate (0.010 g, 0.014 mmol), and pyridine (0.012 ml, 0.145 mmol). MsCl (1.1 μl, 0.014 mmol) was added. The reaction was stirred at 0° C. for 30 minutes and then the reaction was warmed to room temperature. After 1 hour at room temperature, TEA (0.020 ml, 0.145 mmol) was added followed by MsCl (1.1 μl, 0.014 mmol). After 3 hours, more TEA (0.020 ml, 0.145 mmol) was added, followed by more MsCl (5.5 μL, 0.070 mmol). After 1 hour, the reaction was stopped, diluted with EtOAc, washed with 1.5 MK ₂ HPO ₄ , brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a yellow residue. Purified by reverse phase chromatography, concentrated and lyophilized, (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl ) phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-methanesulfonyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2,5,14,16-pentaen-8-one trifluoroacetate and (9R,13S)-13-{4-[5-chloro-2-(4- chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-methanesulfonyl-9-methyl-3, 1 of 4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate: 1 mixture (0.0020 g, 18%) was obtained as a white solid. MS(ESI) m/z: 654.0 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.87 (s, 1H), 8.79 (s, 1H), 8.67 (d, J=5.2 Hz, 2H), 8.34 - 8.32 (m, 2H), 8.28 (s, 1H), 7.90 - 7.87 (m, 4H), 7.75 - 7.71 (m, 2H), 7.66 - 7.63 (m, 3H), 7.62 - 7.60 (m, 1H), 7.55 (dd, J=5.2, 1.7 Hz, 1H), 6.38 - 6.36 (m, 2H), 6.13 - 6.06 (m, 1H), 5.99 - 5.93 (m, 1H), 3.52 (s, 3H), 3.49 (s, 3H), 2.86 - 2.79 (m, 1H), 2.68 - 2.61 (m, 1H), 2.32 - 2.20 (m, 3H), 2.07 - 1.90 (m, 3H), 1.76 - 1.64 (m, 1H), 1.62 - 1.38 (m, 3H), 1.04 ( d, J=6.9 Hz, 3H), 0.98 (d, J=6.9 Hz, 3H), 0.80 - 0.61 (m, 2H). Analytical HPLC (Method A): RT = 7.98 and 8.11 min, purity = 96.9%; Factor XIa Ki = 1.2 nM, plasma kallikrein Ki = 290 nM.

Example 283

(9R,13S)-13-(4-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}- 6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]Preparation of octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl as a solid }-6-oxo-1,6-dihydropyrimidin-1-yl)-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (12 mg, 100% yield) was purified by HATU, DBU coupling methodology as described in Example 56. Using 6-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol ( 0.007 g, 0.02 mmol) and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] It was prepared through coupling of octadeca-1(18),2(6) and 4,14,16-pentaen-8-one (0.07 g, 0.02 mmol). MS m/z = 662.1(M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.34 - 9.30 (m, 1H), 9.15 - 9.11 (m, 1H), 8.74 - 8.71 (m, 1H), 8.63 - 8.59 (m, 1H), 7.85 - 7.79 (m, 2H), 7.72 - 7.67 (m, 1H), 7.64 - 7.61 (m, 1H), 7.38 - 7.35 (m, 1H), 6.62 - 6.58 (m, 1H), 5.88 - 5.73 (m, 1H) ), 2.63 - 2.50 (m, 1H), 2.24 - 2.10 (m, 1H), 2.02 - 1.92 (m, 1H), 1.83 - 1.69 (m, 1H), 1.46 - 1.16 (m, 2H), 0.84 - 0.70 (d, 3H), 0.37 - 0.17 (m, 1H). Analytical HPLC (Method B) RT = 1.73 min, purity = 99%; Factor XIa Ki = 2 nM, plasma kallikrein Ki = 570 nM.

Example 284

Methyl 1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imi Preparation of Dazole-4-carboxylate

Methyl 1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imi Dazole-4-carboxylate trifluoroacetate (10 mg, 24% yield) was purified from 1H-imidazole in a manner similar to the procedure described in Example 231 to 1H-imidazole-4-carboxylate hydrochloride (0.025 g). , 0.195 mmol). MS(ESI) m/z: 613.5 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.80 (s, 1H), 8.68 (d, J=5.3 Hz, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.87 (d, J= 2.2 Hz, 1H), 7.72 (dd, J=8.6, 2.4 Hz, 1H), 7.68 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.51 (dd, J=5.1, 1.5 Hz, 1H), 7.49 (s, 1H), 6.47 (s, 1H), 5.96 (dd, J=12.4, 3.9 Hz, 1H), 4.04 (s, 3H), 3.87 (s, 3H), 2.75 - 2.65 (m , 1H), 2.33 - 2.22 (m, 1H), 2.11 - 1.92 (m, 2H), 1.64 - 1.39 (m, 2H), 1.00 (d, J=6.8 Hz, 3H), 0.67 (br. s., 1H). Analytical HPLC (Method A): RT = 6.10 min, 99.9% purity; Factor XIa Ki = 16 nM, plasma kallikrein Ki = 1,800 nM.

Example 285

(9R,13S)-13-[4-(2,5-dichlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7, Preparation of 15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(2,5-dichlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7, 15-Tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (4.3 mg, 13% yield ) is methyl 1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H -imidazole-4-carboxylate, was the main product isolated from the preparation of Example 284. MS(ESI) m/z: 523.5 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.04 (s, 1H), 8.74 (d, J=5.3 Hz, 1H), 7.73 (s, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.55 - 7.49 (m, 3H), 7.49 - 7.44 (m, 1H), 6.77 (d, J=0.7 Hz, 1H), 6.06 (dd, J=12.7, 4.1 Hz, 1H), 4.05 (s, 3H), 2.78 - 2.68 (m, 1H), 2.38 (tt, J=12.8, 4.3 Hz, 1H), 2.16 - 2.02 (m, 2H), 1.68 - 1.45 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.70 (br. s., 1H). Analytical HPLC (Method A): RT = 8.29 min, 98.6% purity; Factor XIa Ki = 50 nM, plasma kallikrein Ki = 770 nM.

Example 286

(9R,13R)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4, Preparation of 14,16-pentaen-8-one trifluoroacetate

286A. (9R,13R)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 Preparation of ,14,16-pentaen-8-one

(9R,13R)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4 ,14,16-pentaen-8-one (15 mg, 100% yield) was purified from (S)-2-methyl-N-[(1S)-1-[6-( 1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]propane-2-sulfinamide (diastereomer B) (S)- 2-methyl-N-[(1R)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl] Prepared by substituting propane-2-sulfinamide (diastereomer A). MS(ESI) m/z: 300.5 (M+H) ⁺ .

286B. (9R,13R)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, Preparation of 14,16-pentaen-8-one trifluoroacetate

(9R,13R)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, 14,16-pentaen-8-one trifluoroacetate (7.2 mg, 19% yield) was purified from 6-(5-chloro-2-(4-chloro-1H-1) in a manner similar to the procedure described in Example 56. ,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (15.4 mg, 0.050 mmol) and (9R,13R)-13-amino-3,9 prepared as described in Example 286A -Dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (15 mg, 0.050 mmol). MS(ESI) m/z: 590.25 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.47 (s, 1H), 8.72 (s, 1H), 8.66 (s, 1H), 7.94 (t, J=7.9 Hz, 1H), 7.90 (d, J =2.4 Hz, 1H), 7.85 - 7.79 (m, 1H), 7.77 - 7.70 (m, 2H), 7.52 (s, 1H), 7.23 (d, J=7.6 Hz, 1H), 6.48 (s, 1H) , 5.89 (dd, J=12.4, 2.9 Hz, 1H), 4.10 (s, 3H), 3.91 (s, 1H), 3.08 - 2.94 (m, 1H), 2.74 (dt, J=11.4, 5.8 Hz, 1H) ), 1.70 - 1.57 (m, 1H), 1.50 - 1.29 (m, 3H), 1.05 (d, J=6.7 Hz, 3H), 0.98 (m, 1H). Analytical HPLC (Method B): RT 1.64 min, purity = 95%; Factor XIa Ki = 1,800 nM.

Example 287

(9R,13S)-13-(4-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}- 6-oxo-1,6-dihydropyrimidin-1-yl)-3-( ^2H ₃ )methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ]Preparation of octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl as a solid }-6-oxo-1,6-dihydropyrimidin-1-yl)-3-( ^2H ₃ )methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (3 mg, 27% yield) was subjected to the HATU, DBU coupling methodology as described in Example 56. Using 6-{2,3-difluoro-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol ( 0.005 g, 0.015 _mmol ) and (9R,13S)-13-amino-3-( ^2H3 )methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0 ^2,6 ] It was prepared through coupling of octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.004 g, 0.015 mmol). MS m/z = 629.1 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.30 - 9.26 (m, 1H), 9.23 - 9.17 (m, 1H), 8.67 - 8.61 (m, 1H), 8.58 - 8.53 (m, 1H), 7.96 - 7.86 (m, 1H), 7.81 - 7.74 (m, 2H), 7.45 (s, 1H), 6.98 - 6.94 (m, 1H), 6.73 - 6.69 (m, 1H), 5.65 - 5.48 (m, 1H), 2.55 (s, 1H), 2.44 - 2.28 (m, 1H), 2.03 - 1.81 (m, 2H), 1.99 - 1.76 (m, 2H), 1.53 - 1.38 (m, 2H), 1.32 - 1.19 (m, 1H) ), 1.15 - 1.06 (d, 3H), 1.01 - 0.91 (m, 1H). Analytical HPLC (Method B) RT = 1.55 min, purity = 94%; Factor XIa Ki = 4 nM, plasma kallikrein Ki = 520 nM.

Example 288

1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-1H-imidazole -Preparation of 4-carboxylic acid

Methyl 1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7 prepared as described in Example 284 in MeOH (1 ml) ,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6- To a solution of dihydropyrimidin-4-yl}phenyl)-1H-imidazole-4-carboxylate (0.008 g, 9.51 μmol) was added 1 N NaOH (0.057 ml, 0.057 mmol). After stirring at room temperature for 24 hours, the reaction was quenched with a few drops of TFA. Purified by reverse phase chromatography, 1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl} Phenyl)-1H-imidazole-4-carboxylic acid trifluoroacetate (4.8 mg, 61% yield) was obtained as a white solid. MS(ESI) m/z: 599.5 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.76 (s, 1H), 8.71 - 8.66 (m, 2H), 8.11 (br. s., 1H), 7.89 (d, J=2.2 Hz, 1H), 7.77 - 7.72 (m, 1H), 7.70 - 7.65 (m, 2H), 7.51 - 7.48 (m, 2H), 6.58 (s, 1H), 5.97 (dd, J=12.5, 4.2 Hz, 1H), 4.04 (s) , 3H), 2.75 - 2.64 (m, 1H), 2.34 - 2.22 (m, 1H), 2.12 - 1.93 (m, 2H), 1.65 - 1.39 (m, 2H), 1.00 (d, J=6.8 Hz, 3H) ), 0.79 - 0.62 (m, 1H). Analytical HPLC (Method A): RT = 5.13 min, 99.5% purity; Factor XIa Ki = 3.7 nM, plasma kallikrein Ki = 450 nM.

Example 289

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4, Preparation of 14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, 14,16-pentaen-8-one trifluoroacetate (1.8 mg, 5% yield) was purified from 6-(5-chloro-2-(4-chloro-1H-1) in a manner similar to the procedure described in Example 56. ,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol (15.4 mg, 0.050 mmol) and (9R,13S)-13-amino-3,9- prepared as described in Intermediate 28. Dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (15 mg , 0.050 mmol). MS(ESI) m/z: 590.25 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.41 (s, 1H), 8.71 (s, 1H), 8.15 (s, 1H), 7.97 (t, J=7.8 Hz, 1H), 7.90 (d, J =2.4 Hz, 1H), 7.84 - 7.79 (m, 1H), 7.75 (dd, J=8.1, 6.0 Hz, 2H), 7.52 (s, 1H), 7.20 (d, J=7.9 Hz, 1H), 6.48 (s, 1H), 5.97 (d, J=8.5 Hz, 1H), 4.04 (s, 3H), 3.91 (s, 1H), 2.58 (m, 1H), 2.44 - 2.31 (m, 1H), 2.09 ( d, J=7.6 Hz, 1H), 1.83 - 1.73 (m, 1H), 1.53 - 1.39 (m, 2H), 1.23 (m, 1H), 1.00 (d, J=6.7 Hz, 3H). Analytical HPLC (Method B): RT 1.59 min, purity = 93%; Factor XIa Ki = 2.3 nM, plasma kallikrein Ki = 380 nM.

Example 290

(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-10-methyl-3,5,8-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15, Preparation of 17-hexaen-9-one

(10R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-10-methyl-3,5,8-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15, 17-Hexaen-9-one trifluoroacetate (0.004 g, 28%) was prepared as described in Intermediate 38 according to the procedure described in Example 206 (10R,14S)-14-amino-10-methyl- 3,5,8-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2,4,6,15,17-hexaen-9-one, and as described in intermediate 38B Prepared using prepared and 4-bromopyrimidin-5-amine. MS(ESI) m/z: 587.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.18 (s, 1H), 8.71 (s, 1H), 8.35 - 8.31 (m, 2H), 8.01 (s, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.86 - 7.83 (m, 1H), 7.76 - 7.71 (m, 1H), 7.67 - 7.62 (m, 2H), 7.35 (d, J=7.9 Hz, 1H), 6.42 (d, J=0.7 Hz) , 1H), 5.84 (dd, J=13.0, 3.7 Hz, 1H), 2.72 - 2.59 (m, 1H), 2.40 - 2.27 (m, 1H), 2.18 - 2.07 (m, 1H), 2.03 - 1.94 (m , 1H), 1.68 - 1.56 (m, 1H), 1.46 - 1.33 (m, 2H), 1.15 (d, J=7.0 Hz, 3H). Analytical HPLC (Method A): RT = 8.12 min, purity >99%; Factor XIa Ki = 2.4 nM, plasma kallikrein Ki = 150 nM.

Example 292

(9R,13S)-13-{4-[5-chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6), Preparation of 4,14,16-pentaen-8-one

292A and 292B. Preparation of 7-bromo-5-chloro-1-(2-methoxyethyl)-1H-indazole and 7-bromo-5-chloro-2-(2-methoxyethyl)-2H-indazole

1-Bromo-5-chloro-1H-indazole (2.0 g, 8.64 mmol) and K ₂ CO ₃ (5.97 g, 43.2 mmol) in a suspension of DMSO (9.97 mL) at room temperature under a blanket of Ar. Mo-2-methoxyethane (0.812 mL, 8.64 mmol) was added. After 14 hours, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude mixture of regioisomers (1:1) was purified by normal phase chromatography using hexane and EtOAc as eluents to give 7-bromo-5-chloro-1-(2-methoxyethyl)-1H-indazole. as the early eluting isomer (less polar) (0.766 g, 30%), and 7-bromo-5-chloro-2-(2-methoxyethyl)-2H-indazole as the late eluting isomer (more polar) (1.18 g, 47%).

292A. MS(ESI) m/z: 290 (M+H) ⁺ and 292 (M+2+H) ⁺ .

^1H NMR (500MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.66 (d, J=1.7 Hz, 1H), 7.56 (d, J=1.9 Hz, 1H), 4.98 (t, J=6.1 Hz, 2H), 3.85 (t, J=6.1 Hz, 2H), 3.34 (s, 3H).

292B. MS(ESI) m/z: 290 (M+H) ⁺ and 292 (M+2+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) d 8.08 (s, 1H), 7.60 (d, J=1.5 Hz, 1H), 7.48 (d, J=1.8 Hz, 1H), 4.64 - 4.59 (m, 2H), 3.89 - 3.84 (m, 2H), 3.34 (s, 3H).

292C. Preparation of 5-chloro-1-(2-methoxyethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

4,4,4' to a stirred solution of 7-bromo-5-chloro-1-(2-methoxyethyl)-1H-indazole (0.766 g, 2.65 mmol) in dioxane (13.23 mL) at room temperature, 4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.773 g, 3.04 mmol) and KOAc (1.194 g, 12.17 mmol) was added and the system was purged with Ar (3x). Pd(dppf)Cl ₂ .CH2Cl ₂ complex (0.173 g, 0.212 mmol) was added and the reaction was purged with Ar and heated to 90°C.

After stirring overnight, the reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. MS(ESI) m/z: 337 (M+H) ⁺ .

292D. Preparation of 5-chloro-1-(2-methoxyethyl)-7-(6-methoxypyrimidin-4-yl)-1H-indazole

4-Chloro-6-methoxypyrimidine (0.574 g, 3.97 mmol), 5-chloro-1-(2-methoxyethyl)-7-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-1H-indazole (0.891 g, 2.65 mmol) and 2 M aqueous Na ₂ CO ₃ (2.65 mL, 5.29 mmol) were dissolved in DME (17.65 mL)/EtOH (2.206 mL). and purged with Ar for several minutes. Pd(dppf)·CH ₂ Cl ₂ adduct (0.216 g, 0.265 mmol) was added and the reaction was heated at 90°C. After 14 hours, the reaction was diluted with water, extracted with EtOAc and the organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a brown oil. The crude material was purified by normal phase chromatography using hexane and EtOAc as eluents to give 5-chloro-1-(2-methoxyethyl)-7-(6-methoxypyrimidin-4-yl)-1H- The sol (0.777 g, 92% yield) was obtained as a brown oil. MS(ESI) m/z: 319 (M+H) ⁺ .

292E. Preparation of 6-(5-chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl)pyrimidin-4-ol trifluoroacetate

A suspension of 5-chloro-1-(2-methoxyethyl)-7-(6-methoxypyrimidin-4-yl)-1H-indazole (0.300 g, 0.941 mmol) in ACN (3.14 mL) at room temperature. TMSI (1 mL, 7.35 mmol) was added. The clear yellow solution was then heated to 50°C. After 4 hours, the reaction mixture was cooled to room temperature, concentrated and reversed phase chromatography (Phenomenex® Luna Axia C18 5μ 30 x 100mm column, 10-min gradient; Solvent A: 30% MeOH - 70% H ₂ O - 0.1% TFA; Solvent B: 90% MeOH - 10% H ₂ O - 0.1% TFA) to give 6-(5-chloro-1-(2-hydroxyethyl)-1H-indazole-7- I)pyrimidin-4-ol trifluoroacetate (0.127 g, 33.3% yield) was obtained as a yellow solid. MS(ESI) m/z: 291 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.52 (d, J=0.9 Hz, 1H), 8.17 (s, 1H), 7.95 (d, J=2.0 Hz, 1H), 7.47 (d, J=2.0 Hz) , 1H), 6.79 (d, J=0.9 Hz, 1H), 4.45 (t, J=5.9 Hz, 2H), 3.80 (t, J=5.9 Hz, 2H).

292F. (9R,13S)-13-{4-[5-chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6), Preparation of 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-1-(2-hydroxyethyl)-1H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,14,16-pentaen-8-one trifluoroacetate (6.6 mg, 29%) was reacted with 6-(5-chloro-1-(2-hydroxyethyl)-1H- in a manner similar to Example 56. indazol-7-yl)pyrimidin-4-ol trifluoroacetate and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3 prepared as described in Intermediate 30 , 4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one was used to prepare it. MS(ESI) m/z: 609 (M+H) ⁺ .

^1H NMR (400MHz, DMSO-d ₆ ) δ 9.36 (s, 1H), 9.02 (s, 1H), 8.70 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.93 (d, J =2.0 Hz, 1H), 7.85 (s, 1H), 7.69 (s, 1H), 7.40 - 7.35 (m, 2H), 6.68 (s, 1H), 5.93 (d, J=8.6 Hz, 1H), 4.40 - 4.28 (m, 2H), 3.50 - 3.39 (m, 2H), 2.64 - 2.58 (m, 1H), 2.38 - 2.30 (m, 1H), 2.11 - 1.99 (m, 1H), 1.96 - 1.85 (m, 1H), 1.50 - 1.39 (m, 1H), 1.36 - 1.27 (m, 1H), 0.83 (d, J=7.0 Hz, 3H), 0.38 - 0.28 (m, 1H). Analytical HPLC (Method A): RT = 7.16 min, purity = >95%; Factor XIa Ki = 180 nM.

Example 293

(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-( difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-penta Preparation of en-8-one

293A. Preparation of 5-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

4,4,4',4',5,5,5',5' in a solution of 7-bromo-5-chloro-1H-indole (0.470 g, 2.039 mmol) in dioxane (10.20 mL) at room temperature. -Octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.595 g, 2.345 mmol) and KOAc (0.921 g, 9.38 mmol) were added and the system was purged with Ar (3x). did. Pd(dppf)Cl ₂ .CH ₂ Cl ₂ complex (0.133 g, 0.163 mmol) was added and the reaction mixture was purged again with Ar and heated to 90°C. After stirring overnight, the reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAc (3x), the organics were washed with water, brine, dried over Na ₂ SO ₄ , filtered, concentrated and the crude was carried forward to subsequent reactions. MS(ESI) m/z: 278 (M+H) ⁺ .

293B. Preparation of 5-chloro-7-(6-methoxypyrimidin-4-yl)-1H-indole

4-Chloro-6-methoxypyrimidine (0.391 g, 2.70 mmol), 5-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1H-indole (0.500 g, 1.801 mmol) and 2 M aqueous Na ₂ CO ₃ (1.801 ml, 3.60 mmol) were added to DME (14.41 mL)/EtOH (1.801 mL) and purged with Ar for several minutes. PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.147 g, 0.180 mmol) was added and heated at 90°C. After 2 hours, the reaction was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by normal phase chromatography using hexane and EtOAc as eluents to give 5-chloro-7-(6-methoxypyrimidin-4-yl)-1H-indole (0.339 g, 72.5% yield) as an amber color. Obtained as a solid. MS(ESI) m/z: 260 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 11.21 (br. s., 1H), 11.36 - 11.06 (m, 1H), 8.91 (d, J=1.1 Hz, 1H), 7.77 - 7.74 (m, 1H), 7.72 (d, J=1.8 Hz, 1H), 7.40 - 7.38 (m, 1H), 7.30 (d, J=1.1 Hz, 1H), 6.56 (dd, J=3.1, 2.4 Hz, 1H), 4.07 (s , 2H).

293C. Preparation of 6-(5-chloro-1-methyl-1H-indol-7-yl)pyrimidin-4-ol

MeI (0.212 ml, 3.39 mmol) was reacted with 5-chloro-7-(6-methoxypyrimidin-4-yl)-1H-indole (0.339 g, 1.305 mmol) and K ₂ CO in DMSO (5.22 mL) at room temperature. ₃ (0.902 g, 6.53 mmol) was added to the suspension. After stirring overnight, the reaction mixture was partitioned between dilute NH ₄ Cl solution and EtOAc. The organic layer was diluted with dilute NaHCO ₃ and Na ₂ S ₂ O ₃ solutions, NaHCO ₃ , brine, then dried over MgSO ₄ , filtered and evaporated to dryness. The residue was dissolved in AcOH (5 mL), treated with 45% aqueous HBr i (1.73 mL, 14.36 mmol) and heated to 85°C. After 2 hours, the reaction was cooled to room temperature and then concentrated to dryness and the material was carried over to the reaction. MS(ESI) m/z: 260 (M+H) ⁺ .

293D. (9R,13S)-13-[4-(5-chloro-1-methyl-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-( difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-penta Preparation of en-8-one trifluoroacetate

(9R,13S)-13-[4-(5-chloro-1-methyl-1H-indol-7-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3-( difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-penta En-8-one trifluoroacetate (4 mg, 18%) was reacted with 6-(5-chloro-1-methyl-1H-indol-7-yl)pyrimidine-4- in a similar manner as described in Example 56. (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ² prepared as described in All and Intermediate 30 ^,6 ] prepared using octadeca-1(18),2(6),4,14,16-pentaen-8-one. MS(ESI) m/z: 578 (M+H) ⁺ .

^1H NMR (400MHz, DMSO-d ₆ ) δ 9.36 (s, 1H), 8.98 (s, 1H), 8.70 (d, J=5.1 Hz, 1H), 7.85 (s, 1H), 7.69 (s, 1H) ), 7.65 (d, J=2.0 Hz, 1H), 7.39 - 7.35 (m, 2H), 7.03 (d, J=2.0 Hz, 1H), 6.57 (s, 1H), 6.46 (d, J=3.1 Hz) , 1H), 5.94 - 5.90 (m, 1H), 3.53 (s, 3H), 2.63 - 2.60 (m, 1H), 2.35 - 2.30 (m, 1H), 2.06 - 2.02 (m, 1H), 1.95 - 1.88 (m, 1H), 1.46 - 1.40 (m, 1H), 1.34 - 1.28 (m, 1H), 0.82 (d, J=6.8 Hz, 3H), 0.37 - 0.29 (m, 1H). Analytical HPLC (Method A): RT = 9.19 min, purity = >95%; Factor XIa Ki = 390 nM.

Example 294

(9R,13S)-13-{4-[5-chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6), Preparation of 4,14,16-pentaen-8-one

294A. Preparation of 5-chloro-2-(2-methoxyethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole

5-Chloro-2-(2-methoxyethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole 7-Bromo-5-chloro-1-(2-methoxyethyl)-1H-indazole prepared as described in Example 292B in a manner similar to Example 292C was reacted with 7-bromo-5-chloro-1-(2-methoxyethyl)-1H-indazole prepared as described in Example 292C. Prepared by replacing bromo-5-chloro-2-(2-methoxyethyl)-2H-indazole. MS(ESI) m/z: 337 (M+H) ⁺ .

294B. Preparation of 5-chloro-2-(2-methoxyethyl)-7-(6-methoxypyrimidin-4-yl)-2H-indazole

5-Chloro-2-(2-methoxyethyl)-7-(6-methoxypyrimidin-4-yl)-2H-indazole (300 mg, 26%) was prepared in a manner similar to that described in Example 292D. Using 5-chloro-2-(2-methoxyethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole It was manufactured. MS(ESI) m/z: 319 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.87 (d, J=1.1 Hz, 1H), 8.39 (t, J=1.8 Hz, 2H), 8.09 (s, 1H), 7.75 (d, J=2.0 Hz, 1H), 4.63 (t, J=5.2 Hz, 2H), 4.06 (s, 3H), 3.92 - 3.88 (m, 2H), 3.35 (s, 3H).

294C. Preparation of 6-(5-chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl)pyrimidin-4-ol

6-(5-chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl)pyrimidin-4-ol (50 mg, 18%) was reacted with 5-chloro in a manner similar to Example 292E. Prepared using -2-(2-methoxyethyl)-7-(6-methoxypyrimidin-4-yl)-2H-indazole. MS(ESI) m/z: 291 (M+H) ⁺ and 293 (M+2+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.71 (s, 1H), 8.46 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 8.05 (s, 1H), 8.01 (d, J= 1.8 Hz, 1H), 4.65 (t, J=5.2 Hz, 2H), 4.14 - 4.09 (m, 2H).

294D. (9R,13S)-13-{4-[5-chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6), Preparation of 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,14,16-pentaen-8-one trifluoroacetate was reacted with 6-(5-chloro-2-(2-hydroxyethyl)-2H-indazol-7-yl) in a manner similar to Example 56. Pyrimidin-4-ol and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo prepared as described in Intermediate 30 [12.3.1.0 ^2,6 ] Octadeca-1(18),2(6),4,14,16-pentaen-8-one was used to prepare it (2 mg, 8.8%). MS(ESI) m/z: 609 (M+H) ⁺ .

^1H NMR (400MHz, DMSO-d ₆ ) δ 9.36 (s, 1H), 9.00 (s, 1H), 8.69 (d, J=5.1 Hz, 1H), 8.49 (s, 1H), 8.21 (d, J =2.2 Hz, 1H), 8.03 - 7.97 (m, 2H), 7.85 (s, 1H), 7.68 (s, 1H), 7.37 (d, J=6.2 Hz, 1H), 5.92 - 5.89 (m, 1H) , 4.48 (t, J=5.3 Hz, 2H), 3.82 (t, J=5.3 Hz, 2H), 2.62 - 2.59 (m, 1H), 2.34 - 2.29 (m, 1H), 2.07 - 2.02 (m, 1H) ), 1.91 - 1.87 (m, 1H), 1.47 - 1.41 (m, 1H), 1.34 - 1.29 (m, 1H), 0.83 (d, J=6.8 Hz, 3H), 0.38 - 0.30 (m, 1H). Analytical HPLC (Method A): RT = 7.86 min, purity = >95%; Factor XIa Ki = 6,100 nM.

Example 295

(9R,13S)-13-[4-(6-chloro-1-methyl-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3- (difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2, 6]octadeca-1(18),2(6),4,14,16- Preparation of pentaen-8-one

295A. Preparation of 6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

6-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was reacted with 7- Prepared by replacing bromo-5-chloro-1H-indole with 4-bromo-6-chloro-1H-indazole. MS(ESI) m/z: 197 (MC ₆ H ₁₀ +H) ⁺ .

295B. Preparation of 6-chloro-4-(6-methoxypyrimidin-4-yl)-1H-indazole

6-Chloro-4-(6-methoxypyrimidin-4-yl)-1H-indazole (183 mg, 33%) was reacted with 6-chloro-4-(4,4) in a similar manner as described in Example 293B. , 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole was used. MS(ESI) m/z: 261 (M+H) ⁺ .

295C. Preparation of 6-(6-chloro-1-methyl-1H-indazol-4-yl)pyrimidin-4-ol

MeI (0.12 mL, 1.825 mmol) was incubated with 6-chloro-4-(6-methoxypyrimidin-4-yl)-1H-indazole (0.183 g, 0.702 mmol) and K ₂ in DMSO (2.81 mL) at room temperature. CO ₃ (0.485 g, 3.51 mmol) was added to the suspension. After stirring overnight, the reaction mixture was partitioned between dilute aqueous NH ₄ Cl solution and EtOAc. The organic layer was washed with dilute NaHCO ₃ and Na ₂ S ₂ O ₃ solutions, NaHCO ₃ , brine, then dried over MgSO ₄ , filtered and evaporated to dryness. A mixture of these regioisomers (2:1) was carried over to the subsequent reaction. The residue was dissolved in AcOH (3 mL), treated with 45% aqueous HBr (0.932 ml, 7.72 mmol) and heated to 85°C. After 1 hour, the reaction mixture was concentrated to dryness and the crude reaction mixture was purified by reverse phase chromatography (Phenomenex® Luna Axia C18 5μ 30 x 100mm column, 10-min gradient; Solvent A: 30% ACN - 70% H ₂ O - 0.1% TFA; Solvent B: 80% ACN - 20% H ₂ O - 0.1% TFA) to give the desired isomer, 6-(6-chloro-1-methyl-1H-indazol-4-yl) pyri. Mydin-4-ol (0.127 g, 69.4%) as a white solid and the undesired isomer, 6-(6-chloro-2-methyl-2H-indazol-4-yl)pyrimidin-4-ol ( 0.051 g, 27.9%) was obtained as an off-white solid. The methyl group was more downfield for the undesired isomer compared to the desired isomer. MS(ESI) m/z: 261 (M+H) ⁺ .

1H NMR: (400MHz, DMSO-d ₆ ) d 12.69 (br. s., 1H), 8.51 (d, J=0.9 Hz, 1H), 8.37 (d, J=0.7 Hz, 1H), 8.03 - 7.99 ( m, 1H), 7.77 - 7.74 (m, 1H), 6.99 (d, J=0.9 Hz, 1H), 4.09 (s, 3H).

295D. (9R,13S)-13-[4-(6-chloro-1-methyl-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3- (difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16- Preparation of pentaen-8-one trifluoroacetate

(9R,13S)-13-[4-(6-chloro-1-methyl-1H-indazol-4-yl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3- (difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16- Pentaen-8-one trifluoroacetate was reacted with 6-(6-chloro-1-methyl-1H-indazol-4-yl) pyrimidin-4-ol in a manner similar to Example 56 and as described in Intermediate 30. (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 prepared together It was prepared using (18),2(6),4,14,16-pentaen-8-one (1.5 mg, 6.9%). MS(ESI) m/z: 579 (M+H) ⁺ . Analytical HPLC (Method A): RT = 8.40 min, purity = >95%; Factor XIa Ki = 7,400 nM.

Example 296

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-4-(6-hydroxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca- Preparation of 1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]- prepared as described in Example 233 6-oxo-1,6-dihydropyrimidin-1-yl}-4-(6-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3 .1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one was dissolved in THF (1 mL) and HCl (0.5 mL). The solution was heated to 70° C. for 8 hours, then cooled to room temperature, concentrated and purified by reverse phase chromatography to give (9R,13S)-13-{4-[5-chloro-2-(4-chloro- 1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(6-hydroxypyridin-3-yl)- 9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one trifluoroacetate (2.2 mg, 21%) was obtained. MS(ESI) m/z: 669.3 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.55 - 9.54 (m, 1H), 9.52 (s, 1H), 8.76 - 8.65 (m, 2H), 8.58 (d, J=5.2 Hz, 1H), 8.38 (s, 1H), 8.03 (d, J=9.8 Hz, 1H), 7.98 (d, J=2.7 Hz, 1H), 7.92 (d, J=2.1 Hz, 1H), 7.87 (s, 1H), 7.84 - 7.78 (m, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.56 (d, J=5.2 Hz, 1H), 6.57 (d, J=9.8 Hz, 1H), 6.36 (s, 1H) , 6.03 - 5.90 (m, 1H), 2.33 - 2.15 (m, 2H), 1.93 - 1.78 (m, 1H), 1.63 - 1.50 (m, 1H), 1.49 - 1.35 (m, 1H), 0.94 (d, J=6.7 Hz, 3H), 0.65 - 0.49 (m, 1H). Analytical HPLC (Method C): RT = 1.41 min, purity = 95%; Factor XIa Ki = 1 nM, plasma kallikrein Ki = 43 nM.

Example 297

(9R,13S)-13-{4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6), Preparation of 4,14,16-pentaen-8-one

297A. Preparation of 1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]ethan-1-one

A solution of 4-(2 _- bromo-5-chlorophenyl)-6-methoxypyrimidine (0.173 g, 0.578 mmol), CeF (0.351 g, 2.310 mmol) in ClCH ₂ CH 2 Cl (3 mL) was added to Ar. After purging, Pd(PPh ₃ ) ₄ (0.033 g, 0.029 mmol) and 1-(trimethylsilyl)ethanone (0.165 mL, 1.155 mmol) were added. The reaction mixture was purged with Ar, sealed, heated at 75° C. for 2 days, and then cooled to room temperature. Hexane (1 ml) was added and the reaction mixture was filtered through a pad of Celite®, rinsed with 10 ml EtOAc and the filtrate concentrated. Purification by normal phase chromatography gave 1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]ethan-1-one (0.057 g, 38% yield). MS(ESI) m/z: 263.08 (M+H) ⁺ .

297B. Preparation of N'-{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]ethenyl} ethoxycarbohydrazide

1-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)ethanone (0.057 g, 0.217 mmol) and ethyl hydrazinecarboxylate (0.022 g, 0.217 mmol) in EtOH (3 mL) ) to the solution was added 2 drops of concentrated aqueous HCl. The reaction was heated at 75°C for 2 hours. The reaction mixture was then concentrated to obtain crude solid N'-{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]ethenyl}ethoxycarbohydrazide. MS(ESI) m/z: 349.4 (M+H) ⁺ .

297C. Preparation of 4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-methoxypyrimidine

SOCl ₂ (0.076 g, 0.217 mmol) was added to N'-{1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]ethenyl}ethoxycarbohydrazide (0.076 g, 0.217 mmol) in a vial. 0.32 ml, 4.34 mmol) was added, and the resulting solution was stirred at room temperature for 30 minutes and then heated at 60°C for 1 hour. Afterwards, the solution was cooled to room temperature. MeOH was added to the reaction mixture and the solution was concentrated. The residue was purified by reverse phase chromatography to obtain 4-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-1,2,3-thiadiazole (0.017 g, 26% yield. ) was obtained as a yellow solid. MS(ESI) m/z: 305.0 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.87 (s, 1H), 8.63 (d, J=1.1 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.76 (d, J=2.0 Hz) , 1H), 7.71 (dd, J=8.4, 2.2 Hz, 1H), 6.82 (d, J=1.1 Hz, 1H), 4.02 (s, 3H).

297D. Preparation of 6-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]pyrimidin-4-ol

48% aqueous 4-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-1,2,3-thiadiazole (0.059 g, 0.194 mmol) in AcOH (2 ml) HBr (1.1 ml, 9.68 mmol) was added and the solution was heated at 85° C. for 1 hour and then cooled to room temperature. The reaction mixture was concentrated. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO ₃ , brine, dried over MgSO ₄ , filtered and concentrated to give 6-(5-chloro-2-(1,2,3-thiadiazole-4 -yl) phenyl)pyrimidin-4-ol (0.053 g, 94% yield) was obtained as an off-white solid. MS(ESI) m/z: 291.0 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.84 (s, 1H), 7.94 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.55 (dd, J=8.4, 2.2 Hz, 1H), 6.27 (d, J=0.7 Hz, 1H).

297E. (9R,13S)-13-{4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6), Preparation of 4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,14,16-pentaen-8-one trifluoroacetate (0.006 g, 7.7%) was prepared as described in Intermediate 30 according to the procedure described in Example 56 (9R,13S)-13-amino- 3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14, Prepared using 16-pentaen-8-one, and 6-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]pyrimidin-4-ol. MS(ESI) m/z: 609.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD δ 8.93 (s, 1H), 8.87 (s, 1H), 8.74 (d, J=5.1 Hz, 1H), 7.82 - 7.63 (m, 6H), 7.54 - 7.50 (m , 1H), 6.38 (s, 1H), 6.02 (dd, J=12.8, 4.8 Hz, 1H), 2.78 - 2.65 (m, 1H), 2.35 - 2.22 (m, 1H), 2.10 - 1.96 (m, 2H) ), 1.65 - 1.54 (m, 1H), 1.53 - 1.42 (m, 1H), 0.99 (d, J=7.0 Hz, 3H), 0.63 (br. s., 1H). Analytical HPLC (Method A): RT = 8.80 min, purity > 96%, factor XIa Ki = 1.6 nM, plasma kallikrein Ki = 520 nM.

Example 298

(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-oxo-1 ,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), Preparation of 4,14,16-pentaen-8-one

298A. Preparation of 4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-6-methoxypyrimidine

4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-6-methoxypyrimidine (42 mg, 25% yield) was prepared in a manner similar to the procedure described in Example 238 C, replacing 1H-pyrazole-4-carbonitrile with 4-(trifluoromethyl)-1H-pyrazole (37.3 mg, 0.274 mmol). MS(ESI) m/z: 373.3 (M+H) ⁺ .

^1H NMR (400MHz, CDCl ₃ ) δ 8.68 (d, J=1.1 Hz, 1H), 7.76 (s, 1H), 7.70 (s, 1H), 7.62 (dd, J=8.6, 7.7 Hz, 1H), 7.36 (dd, J=8.7, 1.7 Hz, 1H), 6.78 (t, J=1.2 Hz, 1H), 4.01 (s, 3H).

298B. Preparation of 6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyrimidin-4-ol

6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pyrimidin-4-ol (0.017 g, 42.1% yield) Described for the preparation of 1-[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile as described in Intermediate 18C In a similar manner to the procedure, 1-[4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl]-1H-1,2,3-triazole-4-carbonitrile was reacted with 4-(3- It was prepared by replacing chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-6-methoxypyrimidine (0.042 g, 0.113 mmol). MS(ESI) m/z: 359.4 (M+H) ⁺ .

¹ H NMR (400 MHz, CD ₃ OD) δ 8.36 (d, J=0.9 Hz, 1H), 8.09 (d, J=1.1 Hz, 1H), 7.85 (s, 1H), 7.81 - 7.74 (m, 1H) , 7.50 (dd, J=8.7, 1.7 Hz, 1H), 6.50 (t, J=1.1 Hz, 1H).

298C. (9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-oxo-1 ,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ), Preparation of 4,14,16-pentaen-8-one

(9R,13S)-13-(4-{3-chloro-2-fluoro-6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-6-oxo-1 ,6-dihydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6) ),4,14,16-pentaen-8-one (13 mg, 37% yield) was purified from 6-{5-chloro-2-[4-(trifluoromethyl) in a manner similar to the procedure described in Example 56. )-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol to 6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)- It was prepared by replacing with 1H-pyrazol-1-yl)phenyl)pyrimidin-4-ol (17 mg, 0.047 mmol). MS(ESI) m/z: 641.2 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 9.40 (s, 1H), 8.85 (br. s., 1H), 8.72 (d, J=4.8 Hz, 1H), 8.31 (s, 1H), 7.85 - 7.74 (m, 2H), 7.69 (s, 1H), 7.55 - 7.44 (m, 3H), 6.53 (s, 1H), 6.02 (dd, J=12.4, 3.9 Hz, 1H), 4.05 (s, 3H), 2.70 (td, J=6.6, 3.1 Hz, 1H), 2.37 - 2.22 (m, 1H), 2.15 - 1.91 (m, 2H), 1.69 - 1.54 (m, 1H), 1.53 - 1.39 (m, 1H), 1.01 (d, J=6.8 Hz, 3H), 0.70 (m., 1H). Analytical HPLC (Method A): RT = 8.81 min, purity = 99%; Factor XIa Ki = 3.8 nM, plasma kallikrein Ki = 1,200 nM.

Example 299

(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-3, Preparation of 4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

299A. (9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-3- {[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14 , Preparation of 16-pentaen-8-one

(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-3- {[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14 , 16-pentaen-8-one (78 mg, 89% yield) was prepared as described in Intermediate 4 in a manner similar to the procedure described in Example 56. Phenyl)pyrimidin-4-ol (0.033 g, 0.137 mmol), and (9R,13S)-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl} prepared as described in Intermediate 19. -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.057 g, It was prepared using 0.137 mmol). MS(ESI) m/z: 641.6 [M+H] ⁺ .

299B. (9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-3, Preparation of 4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]- in DCM (1.6 mL) 9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2( 6), TFA (0.4 mL, 5.19 mmol) was added to a solution of 4,14,16-pentaen-8-one (78 mg, 0.122 mmol), and the resulting solution was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated and the residue was purified by preparative HPLC purification to give (9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1 ,6-dihydropyrimidin-1-yl]-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,14,16-pentaen-8-one trifluoroacetate (70 mg, 0.112 mmol, 92% yield) was obtained.

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.31 (s, 1H), 8.95 (s, 1H), 8.57 (br. s., 1H), 7.92 - 7.71 (m, 3H), 7.48 (d, J =4.0 Hz, 1H), 7.31 (t, J=8.9 Hz, 1H), 6.70 (s, 1H), 5.99 (br. s., 1H), 2.73 (br. s., 1H), 2.30 (br. s., 2H), 2.01 - 1.88 (m, 1H), 1.60 - 1.37 (m, 2H), 0.93 (d, J=6.7 Hz, 3H), 0.64 (br. s., 1H). MS(ESI) m/z: 511.3 [M+H] ⁺ . Analytical HPLC (Method B): RT = 1.47 min, purity = 94.0%; Factor XIa Ki = 970 nM.

Example 300

(9R,13S)-13-{4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-penta Preparation of en-8-one.

(9R,13S)-13-{4-[5-chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-penta En-8-one trifluoroacetate (0.0072 g, 37.8%) was reacted with (9R,13S)-13-amino-3,9-dimethyl prepared as described in Intermediate 32 in a manner similar to the procedure described in Example 297. -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-prepared using pentaen-8-one did. MS(ESI) m/z: 573.2 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.98 (s, 1H), 8.85 (s, 1H), 8.76 (d, J=5.3 Hz, 1H), 7.82 (d, J=8.1 Hz, 1H), 7.78 (s, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.68 (dd, J=8.1, 2.2 Hz, 1H), 7.61 (dd, J=5.3, 1.5 Hz, 1H), 7.52 (s, 1H), 6.40 (s, 1H), 5.99 (dd, J=12.8, 4.4 Hz, 1H), 4.07 (s, 3H), 2.77 - 2.67 (m, 1H), 2.39 - 2.27 (m, 1H), 2.14 - 2.00 (m, 2H), 1.69 - 1.56 (m, 1H), 1.55 - 1.41 (m, 1H), 1.03 (d, J=7.0 Hz, 3H), 0.76 (br. s., 1H). Analytical HPLC (Method A): RT = 7.46 min, purity >99%; Factor XIa Ki = 1.5 nM, plasma kallikrein Ki = 280 nM.

Example 301

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(2-hydroxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ] Preparation of octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1- prepared as described in Example 323 yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-4-yl)-9-methyl-3,4,7,15-tetra Azatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one (0.02 g, 0.027 mmol) was dissolved in THF (2 mL) and HCl (500 μl, 6.00 mmol) and heated to 70°C for 16 hours. The solvent was concentrated. The residue was purified by reverse phase chromatography to produce (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1 -yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-hydroxypyridin-4-yl)-9-methyl-3,4,7,15- Tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one (1.1 mg, 6%) was obtained. MS(ESI) m/z: 703.0 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.58 (s, 1H), 9.33 - 9.18 (m, 1H), 8.84 - 8.69 (m, 2H), 8.59 (d, J=4.6 Hz, 1H), 7.98 (br. s., 1H), 7.95 - 7.79 (m, 3H), 7.71 - 7.51 (m, 2H), 6.97 - 6.78 (m, 2H), 6.59 - 6.47 (m, 1H), 6.04 (br. s. ., 1H), 2.80 (br. s., 1H), 2.27 (br. s., 2H), 1.97 - 1.75 (m, 2H), 1.57 (br. s., 1H), 1.42 (br. s. , 1H), 0.94 (d, J=6.7 Hz, 3H), 0.53 (br. s., 1H). Analytical HPLC (Method C): RT = 1.58 min, purity = 100%; Factor XIa Ki = 0.16 nM, plasma kallikrein Ki = 8 nM.

Example 302

(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-4- (pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaene-8- manufacture of onion

(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-4- (pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaene-8- Ontrifluoroacetate (13.7 mg, 0.019 mmol, 33% yield) was prepared in a manner analogous to the procedure described in Example 216 with 5-iodopyrimidine (24 mg, 0.117 mmol) and as described in Example 299. (9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-9-methyl-3, 4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (30 mg , 0.059 mmol).

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.58 (s, 1H), 9.35 (s, 2H), 9.15 (s, 1H), 8.97 (s, 1H), 8.76 (s, 1H), 8.63 (d) , J=4.9 Hz, 1H), 7.92 (s, 1H), 7.74 (td, J=8.7, 5.8 Hz, 1H), 7.61 (d, J=4.9 Hz, 1H), 7.29 (t, J=9.0 Hz) , 1H), 6.69 (s, 1H), 6.01 (d, J=11.6 Hz, 1H), 2.77 (br. s., 1H), 2.28 (br. s., 2H), 1.99 - 1.88 (m, 1H) ), 1.54 (br. s., 1H), 1.43 (br. s., 1H), 0.91 (d, J=6.7 Hz, 3H), 0.55 (br. s., 1H). MS(ESI) m/z: 589.2 [M+H] ⁺ . Analytical HPLC (Method B): RT = 1.64 min, purity = 100.0%; Factor XIa Ki = 100 nM, plasma kallikrein Ki = 530 nM.

Example 303

(9R,13S)-13-{4-[5-chloro-2-(pyridazin-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9 -Preparation of dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(5-chloro-2-iodophenyl)-6-oxo-1,6-dihydropyrimidine prepared as described in Example 211 in ACN (1 ml) -1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16 -pentaen-8-one (20 mg, 0.033 mmol), 4-(tributylstannyl)pyridazine (18.01 mg, 0.049 mmol), CuI (1.24 mg, 6.51 μmol), and CsF (9.88 mg, 0.065 mmol) ) was added to the degassed solution of Pd(Ph ₃ P) ₄ (3.76 mg, 3.25 μmol). After stirring at 45°C for 2 hours, the reaction was cooled to room temperature and concentrated. Purified by reverse phase chromatography, (9R,13S)-13-{4-[5-chloro-2-(pyridazin-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1 -yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-penta En-8-one trifluoroacetate (14.9 mg, 67% yield) was obtained. MS(ESI) m/z: 567.35 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.27 - 9.19 (m, 2H), 9.09 (br. s., 1H), 8.76 (s, 1H), 8.67 (d, J=5.2 Hz, 1H), 7.80 (d, J=1.8 Hz, 1H), 7.74 (dd, J=8.2, 2.1 Hz, 1H), 7.68 - 7.56 (m, 4H), 7.48 (s, 1H), 6.50 (s, 1H), 5.92 - 5.83 (m, 1H), 4.01 (s, 3H), 2.69 - 2.60 (m, 1H), 2.31 - 2.22 (m, 1H), 2.14 - 2.04 (m, 1H), 1.89 - 1.78 (m, 1H) , 1.53 - 1.42 (m, 1H), 1.38 - 1.26 (m, 1H), 0.88 (d, J=6.7 Hz, 3H), 0.50 - 0.32 (m, 1H). Analytical HPLC (Method C): RT = 1.28 min, 100% purity; Factor XIa Ki = 110 nM, plasma kallikrein Ki = 9,300 nM.

Example 304

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-4-(2-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca Preparation of -1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-4-(2-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca -1(18),2,5,14,16-pentaen-8-one trifluoroacetate was reacted with 5-iodopyrimidin-2-ol (9.63 mg, 0.043 mg) in a manner similar to the procedure described in Example 216. mmol) using (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo- 1,6-dihydropyrimidin-1-yl}-4-(2-hydroxypyrimidin-5-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2,5,14,16-pentaen-8-one trifluoroacetate (0.9 mg, 1.032 μmol, 2% yield) was obtained.

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.44 (s, 1H), 8.85 - 8.66 (m, 4H), 8.55 (d, J=4.9 Hz, 1H), 8.40 (s, 1H), 7.95 - 7.83 (m, 2H), 7.81 - 7.66 (m, 2H), 7.53 (d, J=4.6 Hz, 1H), 6.34 (s, 1H), 5.95 (br. s., 1H), 2.74 (br. s. , 1H), 2.24 (d, J=14.6 Hz, 2H), 1.80 (br. s., 1H), 1.51 (br. s., 1H), 1.37 (br. s., 1H), 0.89 (d, J=6.4 Hz, 3H), 0.50 (br. s., 1H). MS(ESI) m/z: 670.2 [M+H] ⁺ . Analytical HPLC (Method B): RT = 1.39 min, purity = 90.0%; Factor XIa Ki = 0.17 nM, plasma kallikrein Ki = 14 nM.

Example 305

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,17-triazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3 Preparation of 5,15,17-hexaen-9-one

305A. (S)-tert-butyl (1-(5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)pyridin-3-yl)but-3-en-1-yl )Manufacture of carbamate

5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (2.9 g, 12.84 mmol) and (S)-tert in toluene (38.8 mL) In a solution of -butyl (1-(5-bromopyridin-3-yl)but-3-en-1-yl)carbamate (3.0 g, 9.17 mmol), KOAc (2.70 g, 27.5 mmol) and Pd ( dppf) Cl ₂ .CH ₂ Cl ₂ adduct (0.599 g, 0.733 mmol) was added. The reaction was purged with Ar for 10 minutes and then heated at 90°C for 12 hours. The reaction mixture was diluted with EtOAc and then filtered through Celite®. The filtrate was washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. MS(ESI) m/z: 293 (MC ₆ H ₁₀ +H) ⁺ .

305B. Preparation of (S)-tert-butyl (1-(3'-amino-[3,4'-bipyridin]-5-yl)but-3-en-1-yl)carbamate

(S)-tert-butyl (1-(5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)pyridin-3-yl)but-3-en-1-yl ) Carbamate (1.5 g, 4.16 mmol), 4-bromopyridin-3-amine (0.72 g, 4.16 mmol), 4 M NaHCO ₃ (3.12 mL, 12.49 mmol) were added to dioxane (5 mL) , purged with Ar. After 15 minutes, Pd(PPh ₃ ) ₄ (0.241 g, 0.208 mmol) was added and the mixture was heated at 90° C. overnight. The reaction mixture was diluted with water (100ml), extracted with EtOAc (2x50ml), washed with brine, dried, evaporated to a black oil and carried over to the next reaction. MS(ESI) m/z: 341.2 (M+H) ⁺ .

305C. tert-Butyl ((S)-1-(3'-((R)-2-methylbut-3-enamido)-[3,4'-bipyridin]-5-yl)but-3-ene -1-day) Preparation of carbamate

(R)-2-methylbut-3-enoic acid (0.576 g, 5.76 mmol), (S)-tert-butyl (1-(3'-amino-[3,4'-bipyridine) in EtOAc (43.8 ml) ]-5-yl)but-3-en-1-yl)carbamate (1.4 g, 4.11 mmol) and pyridine (0.998 ml, 12.34 mmol) were cooled to 0°C. T3P® (50 wt% in EtOAc) (5.23 g, 8.23 mmol) was added and the solution was slowly allowed to come to room temperature. After 3 hours, the reaction mixture was concentrated and the residue was purified by normal phase chromatography using EtOAc and MeOH as eluents to give tert-butyl ((S)-1-(3'-((R)-2-methyl But-3-enamido)-[3,4'-bipyridin]-5-yl)but-3-en-1-yl)carbamate (747 mg, 43%) was obtained as a brown oil. MS(ESI) m/z: 423.2 (M+H) ⁺ .

^1H NMR (500MHz, CDCl ₃ ) δ 9.38 (br. s., 1H), 8.66 (s, 1H), 8.57 - 8.47 (m, 2H), 7.62 (br. s., 1H), 7.44 (br. s., 1H), 7.20 (d, J=4.1 Hz, 1H), 5.86 - 5.76 (m, 1H), 5.75 - 5.65 (m, 1H), 5.21 - 5.10 (m, 3H), 3.71 (d, J =11.0 Hz, 3H), 3.09 (t, J=7.3 Hz, 1H), 2.66 - 2.46 (m, 2H), 1.44 - 1.39 (m, 9H), 1.28 (d, J=7.2 Hz, 3H).

305D. tert-Butyl N-[(10R,11E,14S)-10-methyl-9-oxo-5,8,17-triazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2( 7), 3,5,11,15,17-heptaen-14-yl] Preparation of carbamate

tert-Butyl ((S)-1-(3'-((R)-2-methylbut-3-enamido)-[3,4'-bipyridin]-5-yl)but-3-ene -1-yl)carbamate (0.747 g, 1.768 mmol) and pTsOH (0.689 g, 3.62 mmol) were added to EtOAc (1040 mL) and purged with Ar while heating to 60°C. After 1 hour, second generation Grubbs catalyst (0.600 g, 0.707 mmol) was added and the mixture was stirred at 60° C. overnight. The reaction was quenched with saturated NaHCO ₃ (150 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried (Na ₂ SO ₄ ), filtered, and concentrated. The crude material was purified by normal phase chromatography using DCM and MeOH as eluents to give tert-butyl N-[(10R,11E,14S)-10-methyl-9-oxo-5,8,17-triazatricyclo. [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.180 g, 25.8% yield) Obtained as a tan solid. MS(ESI) m/z: 395.2 (M+H) ⁺ .

305E. tert-Butyl N-[(10R,14S)-10-methyl-9-oxo-5,8,17-triazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7) ,3,5,15,17-hexaen-14-yl]Manufacture of carbamate

PtO ₂ (10.36 mg, 0.046 mmol) was dissolved in tert-butyl N-[(10R,11E,14S)-10-methyl-9-oxo-5,8,17-triazatricyclo[13.3) in EtOH (20 mL). .1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,11,15,17-heptaen-14-yl]carbamate (0.180 g, 0.456 mmol) was added to the solution. and treated with H ₂ atmosphere (55 psi). After 3 hours, the suspension was filtered through a plug of Celite® and the filtrate was concentrated and carried over to the subsequent reaction. MS(ESI) m/z: 397.2 (M+H) ⁺ .

305F. (10R,14S)-14-amino-10-methyl-5,8,17-triazatricyclo[13.3.1.0 ^2,7 ] nonadeca-1(19),2(7),3,5,15 , Preparation of 17-hexaen-9-one

TFA (0.70 mL, 9.08 mmol) was dissolved in tert-butyl N-[(10R,14S)-10-methyl-9-oxo-5,8,17-triazatricyclo[13.3. 1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15,17-hexaen-14-yl]carbamate (0.180 g, 0.454 mmol) was added to the stirred solution. After 2 hours, the reaction mixture was concentrated to dryness. The residue was partitioned between EtOAc and saturated NaHCO ₃ . The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give (10R,14S)-14-amino-10-methyl-5,8,17-triazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one (0.037 g, 27.5%) was obtained as a brown film. MS(ESI) m/z: 297.2 (M+H) ⁺ .

305G. (10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,17-triazatricyclo [13.3.1.0 ^2,7 ]nonadeca-1(19),2,4,6, Preparation of 15,17-hexaen-9-one, bis-trifluoroacetate

(10R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-10-methyl-5,8,17-triazatricyclo[13.3.1.0 ^2,7 ]nonadeca-1(19),2,4,6, 15,17-hexaen-9-one, bis-trifluoroacetate was reacted with (10R,14S)-14-amino-10-methyl-5,8,17-triazatricyclo[ 13.3.1.0 ^2,7 ]nonadeca-1(19),2(7),3,5,15,17-hexaen-9-one and 6-{5-chloro- prepared as described in Intermediate 15 Prepared using 2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (5.2 mg, 11%). MS(ESI) m/z: 621.2 (M+H) ⁺ .

^1H NMR (400MHz, DMSO-d ₆ ) δ 9.69 (s, 1H), 9.19 - 9.13 (m, 1H), 8.64 - 8.55 (m, 2H), 8.49 (s, 1H), 8.41 - 8.38 (m, 1H), 8.03 (s, 1H), 7.87 - 7.84 (m, 1H), 7.79 - 7.73 (m, 2H), 7.64 (d, J=4.6 Hz, 1H), 6.42 (s, 1H), 5.51 (d) , J=12.8 Hz, 1H), 1.90 - 1.84 (m, 1H), 1.75 - 1.67 (m, 1H), 1.39 - 1.32 (m, 1H), 1.14 - 1.02 (m, 2H), 0.95 - 0.85 (m , 3H). Analytical HPLC (Method A): RT = 6.96 min, purity = 93%; Factor XIa Ki = 0.17 nM, plasma kallikrein Ki = 25 nM.

Example 306

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-4-(piperidin-4-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1( 18), Preparation of 2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]- prepared as described in Example 101 6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 (18), 2(6),4,14,16-pentaen-8-one (0.020 g, 0.035 mmol), tert-butyl 4-iodopiperidine-1-carboxylate (11 mg, 0.035 mmol), Cs ₂ CO ₃ (0.023 g, 0.069 mmol), and DMF (2 mL) were added to a vial with a Teflon septum-sealed stopper. The mixture was heated to 100° C. for 12 hours, at which time it was cooled to room temperature, DCM (2 mL) and TFA (1 mL) were added and stirred at room temperature for 1 hour. The reaction was then concentrated and purified by reverse phase chromatography to (9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazole-1- 1) phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-9-methyl-4-(piperidin-4-yl)-3,4,7,15-tetraazatri Cyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one trifluoroacetate (3 mg, 14%) was obtained. MS(ESI) m/z: 659.1 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.42 - 9.30 (m, 1H), 8.72 (s, 2H), 8.60 - 8.50 (m, 1H), 7.93 (s, 2H), 7.84 (s, 2H) , 7.78 - 7.72 (m, 1H), 7.48 - 7.40 (m, 1H), 6.36 (s, 1H), 6.05 - 5.85 (m, 1H), 4.64 - 4.45 (m, 1H), 3.17 - 3.02 (m, 2H), 2.82 - 2.70 (m, 1H), 1.94 - 1.75 (m, 1H), 1.62 - 1.48 (m, 1H), 1.47 - 1.34 (m, 1H), 0.93 (d, J=7.0 Hz, 3H) , 0.70 - 0.49 (m, 1H). Analytical HPLC (Method C): RT = 1.31 min, purity = 100%; Factor XIa Ki = 700 nM.

Example 307

1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl) -Preparation of 1H-pyrazole-4-carbonitrile

1-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}-3-fluorophenyl) -1H-Pyrazole-4-carbonitrile trifluoroacetate (2 mg, 43% yield) was reacted with 6-{5-chloro-2-[4-(trifluoromethyl) in a manner similar to the procedure described in Example 56. )-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol was prepared as described in Example 238C with 1-(4-chloro-3-fluoro-2-( Prepared by replacing 6-hydroxypyrimidin-4-yl)phenyl-1H-pyrazole-4-carbonitrile (2 mg, 6.34 μmol) MS(ESI) m/z: 598.1 (M+H) ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ 8.93 - 8.67 (m, 2H), 8.47 (s, 1H), 7.94 (s, 1H), 7.80 (dd, J=8.6, 7.7 Hz, 1H), 7.70 ( s, 1H), 7.57 - 7.45 (m, 3H), 6.54 (s, 1H), 6.00 (dd, J=12.8, 4.2 Hz, 1H), 4.05 (s, 3H), 2.71 (td, J=6.6, 3.3 Hz, 1H), 2.37 - 2.23 (m, 1H), 2.13 - 1.96 (m, 2H), 1.69 - 1.55 (m, 1H), 1.54 - 1.41 (m, 1H), 1.01 (d, J=7.0 Hz) , 3H), 0.71 (m, 1H). Analytical HPLC (Method A): RT = 7.58 min, purity = 97.1%; Factor XIa Ki = 2 nM, plasma kallikrein Ki = 1,500 nM.

Example 308

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-4-(1H-imidazol-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 Preparation of (18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-4-(1H-imidazol-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1 (18),2,5,14,16-pentaen-8-one trifluoroacetate was reacted with 4-iodo-1-trityl-1H-imidazole (18.9 mg) in a manner similar to the procedure described in Example 216. , 0.043 mmol) followed by deprotection using 50% TFA and Et ₃ SiH in DCM as a scavenger to give (9R,13S)-13-{4-[5-chloro-2-(4 -chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(1H-imidazol-4-yl )-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one trifluo Loacetate (3.3 mg, 3.5 μmol, 7% yield) was obtained.

^1H NMR (400MHz, CD ₃ OD) δ 8.75 (s, 1H), 8.69 - 8.62 (m, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 8.03 - 7.90 (m, 3H), 7.79 - 7.74 (m, 1H), 7.73 - 7.66 (m, 2H), 7.55 (br. s., 1H), 6.41 (s, 1H), 6.11 (d, J=9.2 Hz, 1H), 2.88 (d , J=12.1 Hz, 1H), 2.31 (d, J=12.3 Hz, 2H), 2.09 (d, J=12.8 Hz, 1H), 1.74 (br. s., 1H), 1.59 (br. s., 1H), 1.11 (d, J=6.8 Hz, 3H), 0.92 (br. s., 1H). MS(ESI) m/z: 642.2 [M+H] ⁺ . Analytical HPLC (Method A): RT = 5.74 min, purity = 80.0%; Factor XIa Ki = 1.9 nM, plasma kallikrein Ki = 180 nM.

Example 309

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di Hydropyrimidin-1-yl}-9-methyl-4-(1H-1,2,4-triazol-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ] Preparation of octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1 as light brown powder, 6-dihydropyrimidin-1-yl}-9-methyl-4-(1H-1,2,4-triazol-5-yl)-3,4,7,15-tetraazatricyclo [12.3. 1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one (9 mg, 33%) was reacted with 5-iodo- in a manner similar to the procedure described in Example 216. Prepared using 1H-1,2,4-triazole. MS(ESI) m/z: 643.1 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.76 (s, 1H), 8.67 (d, J=5.0 Hz, 1H), 8.58 - 8.48 (m, 1H), 8.41 (s, 1H), 8.36 (s, 1H), 7.98 (s, 1H), 7.91 (d, J=2.2 Hz, 1H), 7.81 - 7.72 (m, 2H), 7.67 (d, J=8.5 Hz, 1H), 6.40 (s, 1H), 6.18 - 6.04 (m, 1H), 2.92 - 2.80 (m, 1H), 2.38 - 2.22 (m, 2H), 2.13 - 2.01 (m, 1H), 1.81 - 1.68 (m, 1H), 1.65 - 1.52 (m , 1H), 1.10 (d, J=6.9 Hz, 3H), 0.91 (d, J=11.8 Hz, 2H). Analytical HPLC (Method A): RT = 6.27 min, purity = 95%; Factor XIa Ki = 3 nM, plasma kallikrein Ki = 220 nM.

Example 310

N-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2, Preparation of 2-trifluoroacetamide

310A. Preparation of N-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide

TEA (0.71 ml, 5.09 mmol) was mixed with 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (1 g, 4.24 mmol) prepared as described in Intermediate 8A in DCM (25 ml); and TFAA (0.72 ml, 5.09 mmol). After stirring at room temperature for 1 hour, the reaction was diluted with DCM, washed with saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated. A yellow solid was obtained as N-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide (1.4 g, 99% yield). MS(ESI) m/z: 332.0 (M+H) ⁺ .

310B. Preparation of N-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide

N-(4-chloro-2-(6-methoxypyrimidin-4-yl)phenyl)-2,2,2-trifluoro in HOAc (10 ml) and 48% aqueous HBr (2.39 ml, 21.10 mmol) A clear yellow solution of loacetamide (1.4 g, 4.22 mmol) was warmed to 60° C. for 3 hours, then cooled to room temperature and the reaction was concentrated. EtOAc (˜400 ml) was added to the residue, followed by saturated NaHCO ₃ . The layers were separated and the organic layer was washed with saturated NaHCO ₃ , brine, dried over MgSO ₄ , filtered and concentrated. The residue was suspended in DCM and the solid was filtered. The filtrate was purified by normal phase chromatography to obtain N-(4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl)-2,2,2-trifluoroacetamide (0.095 g, 7 % yield) was obtained as a white solid. MS(ESI) m/z: 318.0 (M+H) ⁺ .

310C. N-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2, Preparation of 2-trifluoroacetamide trifluoroacetate

N-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa Deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)-2,2, 2-Trifluoroacetamide trifluoroacetate (0.113 g, 63% yield) was purified from N-(4-chloro-2-(6-hydroxypyrimidin-4-yl) in a manner similar to the procedure described in Example 56. ) It was prepared using phenyl)-2,2,2-trifluoroacetamide (0.095 g, 0.301 mmol). MS(ESI) m/z: 600.0 (M+H) ⁺ .

^1H NMR (400MHz, DMSO-d ₆ ) δ 12.37 (s, 1H), 9.23 (s, 1H), 9.07 (s, 1H), 8.70 (d, J=5.1 Hz, 1H), 7.96 - 7.89 (m , 2H), 7.71 (s, 1H), 7.67 - 7.58 (m, 2H), 7.49 (s, 1H), 6.89 (br. s., 1H), 5.95 (d, J=9.5 Hz, 1H), 4.02 (s, 3H), 2.72 - 2.62 (m, 1H), 2.44 - 2.32 (m, 1H), 2.20 - 2.07 (m, 1H), 1.98 - 1.85 (m, 1H), 1.58 - 1.30 (m, 2H) , 0.91 (d, J=6.8 Hz, 3H), 0.58 - 0.39 (m, 1H). Analytical HPLC (Method A): RT = 9.82 min, 100% purity; Factor XIa Ki = 1.7 nM, plasma kallikrein Ki = 180 nM.

Example 311

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(2-hydroxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ] Preparation of octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1- prepared as described in Example 319 yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetra Azatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one (0.02 g, 0.027 mmol) was dissolved in THF (2 mL) and concentrated HCl ( 500 μl, 6.00 mmol) and heated to 70° C. for 16 hours. The reaction was cooled to room temperature and the solution was concentrated. The residue was purified by reverse phase chromatography to produce (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole-1 -yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-4-(2-hydroxypyridin-3-yl)-9-methyl-3,4,7,15- Tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one (15 mg, 64%) was obtained. MS(ESI) m/z: 703.2 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.84 (s, 1H), 8.79 (s, 1H), 8.66 (s, 1H), 8.62 (d, J=5.0 Hz, 1H), 8.31 (dd, J= 7.4, 1.9 Hz, 1H), 7.97 (s, 1H), 7.93 (d, J=2.2 Hz, 1H), 7.80 - 7.75 (m, 1H), 7.75 - 7.68 (m, 2H), 7.48 (dd, J =6.6, 1.9 Hz, 1H), 6.58 (dd, J=7.4, 6.3 Hz, 1H), 6.48 (d, J=0.6 Hz, 1H), 6.16 - 6.04 (m, 1H), 2.91 - 2.77 (m, 1H), 2.34 - 2.21 (m, 2H), 2.11 - 2.00 (m, 1H), 1.79 - 1.66 (m, 1H), 1.63 - 1.51 (m, 1H), 1.10 (d, J=6.9 Hz, 3H) , 0.99 - 0.85 (m, 1H). Analytical HPLC (Method A): RT = 7.36 min, purity = 97.6%; Factor XIa Ki = 19 nM, plasma kallikrein Ki = 800 nM.

Example 312

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-methyl-3-(1H-pyrazol-3-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1 Preparation of (18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-di hydropyrimidin-1-yl}-9-methyl-3-(1H-pyrazol-3-yl)-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1 (18),2(6),4,14,16-pentaen-8-one trifluoroacetate was reacted with 3-iodo-1-trityl-1H-pyrazole in a manner similar to the procedure described in Example 216. (18.9 mg, 0.043 mmol) followed by deprotection using 50% TFA and Et ₃ SiH in DCM as scavenger to give (9R,13S)-13-{4-[5-chloro-2 -(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-(1H-imidazol- 4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaene-8- One trifluoroacetate (5.3 mg, 3.5 μmol, 7% yield) was obtained.

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.31 (s, 1H), 8.69 (s, 1H), 8.58 (s, 1H), 8.52 (d, J=4.9 Hz, 1H), 8.33 (s, 1H) ), 7.89 (br. s., 2H), 7.78 (d, J=8.5 Hz, 1H), 7.74 - 7.66 (m, 1H), 7.53 (d, J=4.9 Hz, 1H), 7.24 - 6.96 (m , 3H), 6.37 (s, 1H), 5.80 (d, J=11.6 Hz, 1H), 3.42 - 3.33 (m, 1H), 2.29 (br. s., 1H), 1.92 (d, J=11.3 Hz) , 1H), 1.79 (br. s., 1H), 1.48 (d, J=9.8 Hz, 1H), 1.30 (br. s., 1H), 1.14 (d, J=6.7 Hz, 3H), 0.97 ( br. s., 1H). MS(ESI) m/z: 642.3 [M+H] ⁺ . Analytical HPLC (Method B): RT = 1.48 min, purity = 99.0%; Factor XIa Ki = 28 nM, plasma kallikrein Ki = 720 nM.

Example 313

(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4, Preparation of 7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

N-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7, prepared as described in Example 310 in MeOH (2 ml) 15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-di To a solution of hydropyrimidin-4-yl}phenyl)-2,2,2-trifluoroacetamide (0.111 g, 0.185 mmol) was added 1.25 M HCl in MeOH (0.5 ml, 0.625 mmol). After stirring at 75°C for 1 hour, the reaction was cooled to room temperature, concentrated, and lyophilized overnight to give (9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo- 1,6-dihydropyrimidin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2( 6),4,14,16-pentaen-8-one hydrochloride (0.1 g, 94% yield) was obtained as a yellow solid. From this material, 10 mg was purified by reverse phase chromatography to obtain (9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidine-1. -yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-penta En-8-one trifluoroacetate was obtained. MS(ESI) m/z: 504.4 (M+H) ⁺ .

¹ H NMR (500 MHz, CD ₃ OD) δ 8.89 (br. s., 1H), 8.63 (d, J=5.0 Hz, 1H), 7.63 (s, 1H), 7.43 - 7.38 (m, 2H), 7.33 (s, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.59 (s, 1H), 5.95 (d, J=9.9 Hz, 1H), 3.95 (s, 3H), 2.67 - 2.60 (m, 1H), 2.31 - 2.21 (m, 1H), 2.06 - 1.91 (m, 2H), 1.59 - 1.34 (m, 2H), 0.92 (d, J=6.9 Hz) , 3H), 0.69 - 0.54 (m, 1H). Analytical HPLC (Method B): RT = 1.45 min, 100% purity; Factor XIa Ki = 57 nM, plasma kallikrein Ki = 2,400 nM.

Example 314

(9R,13S)-13-(4-{5-chloro-2-[(pyrimidin-4-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- manufacture of onion

(9R,13S)-13-[4-(2-amino-5-chlorophenyl)-6-oxo-1,6-dihydropyrimidine- prepared as described in Example 313 in EtOH (1 ml) 1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16- A mixture of pentaen-8-one hydrochloride (0.01 g, 0.017 mmol), 4-bromopyrimidine hydrochloride (6.78 mg, 0.035 mmol) was microwaved at 150° C. for 30 minutes and cooled to room temperature. Concentrated. Purified by reverse phase chromatography, (9R,13S)-13-(4-{5-chloro-2-[(pyrimidin-4-yl)amino]phenyl}-6-oxo-1,6-dihydropyryl midin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14, 16-pentaen-8-one trifluoroacetate (6.3 mg, 45% yield) was obtained. MS(ESI) m/z: 582.2 (M+H) ⁺ .

¹ H NMR (500MHz, CD ₃ OD) δ 8.88 (s, 1H), 8.61 (d, J=5.2 Hz, 1H), 8.56 (s, 1H), 8.15 (d, J=6.1 Hz, 1H), 7.73 - 7.67 (m, 2H), 7.62 (s, 1H), 7.48 (dd, J=8.5, 2.5 Hz, 1H), 7.43 - 7.39 (m, 2H), 6.85 (d, J=6.9 Hz, 1H), 6.61 (s, 1H), 5.89 (d, J=12.9 Hz, 1H), 3.97 - 3.92 (m, 3H), 2.66 - 2.59 (m, 1H), 2.28 - 2.19 (m, 1H), 2.03 - 1.89 ( m, 2H), 1.56 - 1.34 (m, 2H), 0.92 (d, J=7.2 Hz, 3H), 0.71 - 0.56 (m, 1H). Analytical HPLC (Method C): RT = 1.16 min, 100% purity; Factor XIa Ki = 6,000 nM.

Example 315

(9R,13S)-13-{4-[2-(aminomethyl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl )-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- manufacture of onion

315A. Preparation of tert-butyl 4-chloro-2-(6-hydroxypyrimidin-4-yl)benzylcarbamate

In a microwave vial, tert-butyl 2-bromo-4-chlorobenzylcarbamate (0.78 g, 2.43 mmol) was taken and dissolved in dioxane (10 ml) and the solution was purged with Ar for 0.5 h. Then, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.93 g, 3.64 mmol) followed by KOAc (0.64 g, 6.56 mmol) and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ adduct (0.06 g, 0.07 mmol) and the reaction was sealed. The microwave vial was heated at 80°C overnight. LCMS confirmed the formation of the desired boronate/boronic acid, and the reaction was cooled to room temperature. To this was added chloromethoxypyrimidine (0.351 g, 2.43 mmol), followed by 2 M aqueous Na ₂ CO ₃ (3.04 ml) and the reaction mixture was purged with Ar for 0.5 h, followed by Pd(dppf). Cl ₂ .CH ₂ Cl ₂ adduct (0.06 g, 0.07 mmol) was added and the reaction was resealed. The reaction was heated at 120° C. for 1 hour, then cooled to room temperature and the reaction was quenched with water (100 ml). The organic portion was extracted with EtOAc (2x200ml), dried and evaporated to a black oil. Purification with a 40 g silica gel ISCO column eluting with Hex:EtOAc gave the pure product as an oily substance. LCMS m/z = 350.08 (M+H) ⁺ .

315B. Preparation of tert-butyl 4-chloro-2-(6-hydroxypyrimidin-4-yl)benzylcarbamate

Take tert-butyl 4-chloro-2-(6-methoxypyrimidin-4-yl)benzylcarbamate in a small vial and add AcOH (1 ml) followed by 48% aqueous HBr (0.1 ml). and sealed, and heated at 80°C for 1 hour. LCMS confirmed the product peak and mass of 336 (M+H) ⁺ . The solution was cooled and concentrated under a stream of N ₂ to an oily substance and dioxane (3 ml) was added, at which point a solid precipitated out. The solution was decanted and the residue was dissolved in DMF (3 ml) and transferred to a solution of dioxane (2 ml). To this was added Boc ₂ O (0.1 g) followed by TEA (2 ml) and the solution was stirred at room temperature overnight. NaOH solution (1N, 5 ml) was added to this solution, and the reaction was stirred at room temperature for 0.5 hours. Afterwards, the reaction mixture was extracted with EtOAc (2x50ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated to a dark brown oil. Purification by preparative HPLC using a MeOH/water/TFA gradient gave tert-butyl 4-chloro-2-(6-hydroxypyrimidin-4-yl)benzylcarbamate (0.05 g).

^1H NMR (400MHz, CDCl ₃ ) δ 8.46 - 8.32 (m, 1H), 7.54 - 7.41 (m, 3H), 6.76 - 6.67 (m, 1H), 4.31 (s, 2H), 1.44 (s, 9H) . MS m/z = 236.1 (M+H) ⁺ .

315C. (9R,13S)-13-{4-[2-(aminomethyl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl )-9-methyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- manufacture of onion

(9R,13S)-13-{4-[2-(aminomethyl)-5-chlorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3-(difluoromethyl )-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- ion (4 mg, 42% yield) was purified from N-{[4-chloro-2-(6-hydroxypyrimidin-4-yl)phenyl]methyl} using the HATU, DBU coupling methodology described in Example 56. Carbamate (0.005 g, 0.015 mmol) and (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6), 4,14,16-pentaen-8-one (0.005 g, 0.015 mmol) was prepared as a solid through coupling. MS m/z = 554.1 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.53 - 9.43 (m, 1H), 9.11 - 9.04 (m, 1H), 8.82 - 8.71 (m, 1H), 8.42 - 8.23 (m, 1H), 7.98 - 7.83 (m, 1H), 7.79 - 7.70 (m, 1H), 7.68 - 7.59 (m, 1H), 7.37 - 7.01 (m, 2H), 6.84 - 6.74 (m, 1H), 6.08 - 5.91 (m, 1H) ), 4.19 - 3.94 (m, 2H), 2.77 - 2.63 (m, 1H), 2.34 - 2.22 (m, 1H), 2.13 - 1.86 (m, 2H), 1.57 - 1.30 (m, 2H), 0.97 - 0.74 (d 3H), 0.53 - 0.27 (m, 1H). Analytical HPLC (Method B) RT = 1.17 min, purity = 96%: Factor XIa Ki = 43 nM, plasma kallikrein Ki = 4,900 nM.

Example 316

(9R,13S)-13-{4-[5-chloro-2-(pyridin-2-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9- Preparation of dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-chloro-2-(pyridin-2-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9- Dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoro Acetate (13.3 mg, 51% yield) was obtained by replacing 4-(tributylstannyl)pyridazine with 2-(tributylstannyl)pyridine (17.96 mg, 0.049 mmol) in a manner similar to the procedure described in Example 303. Prepared, the reaction time was 2 hours at 45°C and then 6 hours at 90°C. MS(ESI) m/z: 566.15 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.23 (s, 1H), 8.72 (br. s., 1H), 8.67 (d, J=4.9 Hz, 1H), 8.52 (d, J=4.0 Hz, 1H), 7.82 (t, J=7.8 Hz, 1H), 7.72 (s, 1H), 7.67 - 7.62 (m, 3H), 7.56 (d, J=4.9 Hz, 1H), 7.49 - 7.36 (m, 3H) ), 6.25 (s, 1H), 5.86 (d, J=10.1 Hz, 1H), 4.00 (s, 3H), 2.68 - 2.59 (m, 1H), 2.30 - 2.21 (m, 1H), 2.14 - 2.03 ( m, 1H), 1.86 - 1.76 (m, 1H), 1.50 - 1.40 (m, 1H), 1.37 - 1.26 (m, 1H), 0.87 (d, J=7.0 Hz, 3H), 0.52 - 0.33 (m, 1H). Analytical HPLC (Method C): RT = 1.12 min, 100% purity; Factor XIa Ki = 350 nM.

Example 317

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ] Preparation of octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2,5,14,16-pentaen-8-one was reacted with 3-iodo-2-methoxypyridine (39 mg, 0.164 mg) in a manner similar to the procedure described in Example 216. mmol) and (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazole prepared as described in Example 196 -1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] Prepared using octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.05 g, 0.082 mmol) (9R,13S)-13-(4-{5) -chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl) -4-(2-methoxypyridin-3-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2,5 ,14,16-pentaen-8-one trifluoroacetate (49 mg, 71% yield) was obtained as a light green solid. MS(ESI) m/z: 717.5 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.47 (s, 1H), 9.24 (d, J=0.8 Hz, 1H), 8.70 (s, 1H), 8.56 (d, J=5.0 Hz, 1H), 8.42 (s, 1H), 8.25 (dd, J=4.8, 1.8 Hz, 1H), 8.20 (dd, J=7.7, 1.7 Hz, 1H), 7.98 (d, J=2.2 Hz, 1H), 7.91 (s , 1H), 7.89 - 7.81 (m, 2H), 7.58 (dd, J=5.1, 1.5 Hz, 1H), 7.24 (dd, J=7.7, 4.7 Hz, 1H), 6.51 (s, 1H), 6.10 - 5.95 (m, 1H), 4.02 (s, 3H), 2.84 - 2.70 (m, 1H), 2.35 - 2.18 (m, 2H), 1.91 - 1.75 (m, 1H), 1.63 - 1.50 (m, 1H), 1.48 - 1.32 (m, 1H), 0.95 (d, J=7.2 Hz, 3H), 0.69 - 0.45 (m, 1H). Analytical HPLC (Method A): RT = 10.02 min, purity = 99.2%; Factor XIa Ki = 18 nM, plasma kallikrein Ki = 850 nM.

Example 318

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-3-(6-methoxypyrimidin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]Preparation of octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6 as side product -Oxo-1,6-dihydropyrimidin-1-yl)-3-(6-methoxypyrimidin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (0.83 mg, 0.908 μmol, 1% yield) was prepared in Example 216. 4-iodo-6-methoxypyrimidine (19.35 mg, 0.082 mmol) and (9R,13S)-13-(4-{5-chloro-2) as described in Example 196 in a manner similar to the procedure described in -[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl -3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (50 mg, It was prepared using 0.082 mmol).

¹ H NMR (400MHz, CD ₃ OD) δ 8.86 (s, 1H), 8.74 (s, 1H), 8.72 (s, 1H), 8.66 (d, J=5.3 Hz, 1H), 8.59 (s, 1H) , 8.07 (s, 1H), 7.95 (d, J=2.4 Hz, 1H), 7.80 (dd, J=8.5, 2.5 Hz, 2H), 7.76 - 7.70 (m, 1H), 7.45 (s, 1H), 6.50 (s, 1H), 5.93 (d, J=9.0 Hz, 1H), 4.12 (s, 2H), 2.64 (s, 1H), 2.41 (s, 1H), 2.03 (s, 2H), 1.72 (s , 1H), 1.46 (br. s., 2H), 1.34 (d, J=6.8 Hz, 3H), 1.24 (s, 1H). MS(ESI) m/z: 718.3 [M+H] ⁺ . Analytical HPLC (Method A): RT = 9.47 min, purity = 91.0%; Factor XIa Ki = 280 nM, plasma kallikrein Ki = 5,200 nM.

Example 319

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyrimidin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]Preparation of octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6 as main product -Oxo-1,6-dihydropyrimidin-1-yl)-4-(6-methoxypyrimidin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3 .1.0 ^2,6 ]octadeca-1(18),2,5,14,16-pentaen-8-one trifluoroacetate (5.5 mg, 6.28 μmol, 7% yield) according to the procedure described in Example 216. 4-iodo-6-methoxypyrimidine (19.35 mg, 0.082 mmol) and (9R,13S)-13-(4-{5-chloro-2-[4) as described in Example 196 in a similar manner. -(trifluoromethyl)-1H-1,2,3-triazol-1-yl] phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3, 4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (50 mg, 0.082 mmol) It was manufactured using.

¹ H NMR (400MHz, CD ₃ OD) δ 8.86 (d, J=0.9 Hz, 1H), 8.79 - 8.73 (m, 1H), 8.71 (s, 2H), 8.67 (d, J=5.1 Hz, 1H) , 7.99 - 7.91 (m, 2H), 7.83 - 7.77 (m, 1H), 7.76 - 7.70 (m, 2H), 7.43 (d, J=0.9 Hz, 1H), 6.49 (d, J=0.7 Hz, 1H) ), 6.15 (d, J=8.1 Hz, 1H), 4.11 (s, 3H), 2.88 (d, J=3.3 Hz, 1H), 2.30 (t, J=12.7 Hz, 2H), 2.06 (t, J =11.8 Hz, 1H), 1.82 - 1.68 (m, 1H), 1.60 (br. s., 1H), 1.10 (d, J=7.0 Hz, 3H), 0.84 (br. s., 1H). MS(ESI) m/z: 718.3 [M+H] ⁺ . Analytical HPLC (Method A): RT = 9.90 min, purity = 95.0%; Factor XIa Ki = 4 nM, plasma kallikrein Ki = 100 nM.

Example 320

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(6-hydroxypyrimidin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]Preparation of octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(6-hydroxypyrimidin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2,5,14,16-pentaen-8-one trifluoroacetate (5.4 mg, 6.47 μmol, 26% yield) was prepared in a manner similar to the procedure described in Example 296. It was manufactured with .

¹ H NMR (400MHz, CD ₃ OD) δ 8.85 (d, J=0.9 Hz, 1H), 8.73 (s, 1H), 8.67 (d, J=5.3 Hz, 1H), 8.60 (s, 1H), 8.29 (d, J=0.9 Hz, 1H), 7.97 (s, 1H), 7.94 (d, J=2.4 Hz, 1H), 7.81 - 7.76 (m, 1H), 7.76 - 7.69 (m, 2H), 7.00 ( d, J=0.7 Hz, 1H), 6.48 (s, 1H), 6.17 - 6.09 (m, 1H), 2.86 (d, J=3.5 Hz, 1H), 2.35 - 2.22 (m, 2H), 2.12 - 1.99 (m, 1H), 1.81 - 1.53 (m, 3H), 1.09 (d, J=7.0 Hz, 3H), 0.86 (br. s., 1H). MS(ESI) m/z: 704.5 [M+H] ⁺ . Analytical HPLC (Method A): RT = 7.47 min, purity = 98.0%; Factor XIa Ki = 0.2 nM, plasma kallikrein Ki = 39 nM.

Example 321

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ] Preparation of octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo- 1,6-dihydropyrimidin-1-yl)-4-(2-methoxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]Octadeca-1(18),2,5,14,16-pentaen-8-one (4 mg, 6%) was 4-iodo-2-methyl in a manner similar to the procedure described in Example 216. Toxypyridine (39 mg, 0.164 mmol) and (9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2 as described in Example 196 ,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3. 1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one (0.05 g, 0.082 mmol) was used to prepare it. MS(ESI) m/z: 717.1 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.60 (s, 1H), 9.24 (s, 1H), 8.85 (s, 1H), 8.71 (s, 1H), 8.60 (d, J=4.9 Hz, 1H ), 8.31 (d, J=5.5 Hz, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.90 - 7.80 (m, 2H), 7.62 (dd, J=18.3, 4.9 Hz, 2H) , 7.36 (s, 1H), 6.51 (s, 1H), 6.03 (br. s., 1H), 3.94 (s, 3H), 3.46 - 3.27 (m, 2H), 2.81 (br. s., 1H) , 2.27 (d, J=18.9 Hz, 2H), 1.85 (br. s., 1H), 1.57 (br. s., 1H), 1.42 (br. s., 1H), 0.95 (d, J=6.4 Hz, 3H), 0.54 (br. s., 1H). Analytical HPLC (Method C): RT = 1.81 min, purity = 100%; Factor XIa Ki = 0.6 nM, plasma kallikrein Ki = 17 nM.

Preparation of Examples 322-352

The following compounds were prepared in a parallel manner using the following procedure: Reagents were weighed in BIOTAGE® 0.5 - 2 mL microwave vials. A stock solution was prepared for reagent addition: 472.9 mg core dissolved in 18.6 mL 1,4-dioxane (0.04M). 265.7 mg potassium carbonate dissolved in 6.2 mL 0.3 M water. To each microwave vial containing the reagents, Si-DPP-Pd (12.40 mg, 3.72 μmol) was added via ArgoScoop, 0.600 mL core solution, and 0.200 mL potassium carbonate solution. The reaction was queued to run on a Biotage® initiator (400 W) microwave at 120° C. with a pre-stirring and hold time of 10 seconds.

Upon completion of the microwave run, the reaction mixture was concentrated, then redissolved in 1.8 mL DMF and filtered through a 45 μM syringe filter. The resulting clear solution was purified via preparative LC/MS with the following conditions: Column: Xbridge C18, 19 x 100 mm, 5-μm particles; Mobile phase A: 5:95 acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Gradient: 40-80% B over 10 minutes, followed by a 5-minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The gradient was changed for each reaction depending on the polarity of the compound.

Compound purity was assigned based on the following method.

Method A: Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-μm particles; Mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50℃; Gradient: 0-100% B over 3 min, then 0.75-min hold at 100% B; Flow rate: 1.11 mL/min; Detection: UV at 220 nm.

Method B: Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-μm particles; Mobile phase A: 5:95 acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50℃; Gradient: 0-100% B over 3 min, then 0.75-min hold at 100% B; Flow rate: 1.11 mL/min; Detection: UV at 220 nm.

Example 322

(9R,13S)-13-{4-[5-chloro-2-(4-methylphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl- Preparation of 3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 579.1 (M+H) ⁺ .

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.14 (s, 1H), 8.82 (s, 1H), 8.62 (d, J=5.2 Hz, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.57 (s, 1H), 7.53 - 7.49 (m, 2H), 7.40 (s, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.10 - 7.03 (m, 4H), 5.99 (s, 1H) , 5.79 (d, J=10.1 Hz, 1H), 3.94 (s, 3H), 2.61 - 2.53 (m, 1H), 2.26 - 2.17 (m, 4H), 2.07 - 1.99 (m, 1H), 1.80 - 1.72 (m, 1H), 1.44 - 1.35 (m, 1H), 1.31 - 1.21 (m, 1H), 0.81 (d, J=6.7 Hz, 3H), 0.41 - 0.26 (m, 1H). Analytical HPLC (Method A): RT =2.02 min, purity =98.7%; Factor XIa Ki = 180 nM.

Example 323

(9R,13S)-13-{4-[5-chloro-2-(3-chlorophenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl Preparation of -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 599.1 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.15 (s, 1H), 8.76 (s, 1H), 8.60 (d, J=4.9 Hz, 1H), 7.63 (d, J=2.1 Hz, 1H), 7.59 - 7.54 (m, 2H), 7.50 (dd, J=5.2, 0.9 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.34 - 7.26 (m, 2H), 7.23 (s, 1H), 7.09 ( d, J=7.3 Hz, 1H), 6.16 (s, 1H), 5.79 (d, J=11.0 Hz, 1H), 3.94 (s, 3H), 2.61 - 2.53 (m, 1H), 2.27 - 2.17 (m , 1H), 2.07 - 1.97 (m, 1H), 1.80 - 1.70 (m, 1H), 1.44 - 1.34 (m, 1H), 1.31 - 1.20 (m, 1H), 0.81 (d, J=6.7 Hz, 3H) ), 0.43 - 0.29 (m, 1H). Analytical HPLC (Method A): RT =2.03 min, purity =94.8%; Factor XIa Ki = 7,500 nM.

Example 324

(9R,13S)-13-{4-[5-chloro-2-(3-methoxyphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9- Preparation of dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 595.1 (M+H) ⁺ .;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.15 (s, 1H), 8.81 (s, 1H), 8.61 (d, J=5.2 Hz, 1H), 7.61 (d, J=2.1 Hz, 1H), 7.58 (s, 1H), 7.55 - 7.49 (m, 2H), 7.41 - 7.37 (m, 2H), 7.18 (t, J=7.9 Hz, 1H), 6.80 (dd, J=8.2, 2.1 Hz, 1H) , 6.73 (d, J=7.6 Hz, 1H), 6.69 (s, 1H), 6.04 (s, 1H), 5.78 (d, J=10.1 Hz, 1H), 3.94 (s, 3H), 3.58 (s, 3H), 2.60 - 2.53 (m, 1H), 2.27 - 2.18 (m, 1H), 2.07 - 1.98 (m, 1H), 1.81 - 1.71 (m, 1H), 1.44 - 1.34 (m, 1H), 1.31 - 1.21 (m, 1H), 0.81 (d, J=6.7 Hz, 3H), 0.43 - 0.29 (m, 1H); Analytical HPLC (Method A): RT =1.91 min, purity =97.5%; Factor XIa Ki = 550 nM.

Example 325

(9R,13S)-13-{4-[5-chloro-2-(2-methylphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl- Preparation of 3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 579.1 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.20 (s, 1H), 8.91 (s, 1H), 8.68 (d, J=5.2 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.63 - 7.55 (m, 3H), 7.46 (s, 1H), 7.31 - 7.18 (m, 4H), 7.11 (s, 1H), 5.85 - 5.78 (m, 2H), 4.00 (d, J=3.1 Hz, 3H), 2.67 - 2.60 (m, 1H), 2.32 - 2.22 (m, 1H), 2.13 - 2.03 (m, 1H), 1.95 (d, J=12.8 Hz, 3H), 1.86 - 1.76 (m, 1H) , 1.49 - 1.39 (m, 1H), 1.37 - 1.28 (m, 1H), 0.87 (d, J=6.7 Hz, 3H), 0.46 - 0.31 (m, 1H); Analytical HPLC (Method A): RT =2.05 min, purity =100%; Factor XIa Ki = 3,900.

Example 326

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethoxy)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4,14,16-pentaene-8- manufacture of onion

MS(ESI) m/z: 649 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.21 (s, 1H), 8.83 (s, 1H), 8.66 (d, J=4.9 Hz, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.67 - 7.61 (m, 2H), 7.59 (d, J=4.9 Hz, 1H), 7.51 - 7.46 (m, 2H), 7.38 - 7.30 (m, 4H), 6.22 (s, 1H), 5.88 (d, J=10.4 Hz, 1H), 4.01 (s, 3H), 2.69 - 2.60 (m, 1H), 2.32 - 2.23 (m, 1H), 2.16 - 2.06 (m, 1H), 1.86 - 1.77 (m, 1H) , 1.52 - 1.42 (m, 1H), 1.38 - 1.28 (m, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.48 - 0.34 (m, 1H); Analytical HPLC (Method A): RT =2.14 min, purity =100%.; Factor XIa Ki = 640.

Example 327

(9R,13S)-13-{4-[5-chloro-2-(2-chlorophenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl Preparation of -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 599 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.20 (s, 1H), 8.89 (d, J=5.5 Hz, 1H), 8.70 - 8.66 (m, 1H), 7.85 (s, 1H), 7.66 - 7.61 (m, 2H), 7.57 (d, J=4.6 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.43 - 7.29 (m, 4H), 5.93, 5.91 (2s, 1H), 5.84 (d, J =11.0 Hz, 1H), 4.01, 4.00 (2s, 3H), 2.66 - 2.60 (m, 1H), 2.32 - 2.22 (m, 1H), 2.13 - 2.04 (m, 1H), 1.85 - 1.75 (m, 1H) ), 1.50 - 1.40 (m, 1H), 1.37 - 1.27 (m, 1H), 0.87 (d, J=6.7 Hz, 3H), 0.45 - 0.31 (m, 1H); Analytical HPLC (Method A): RT =2.01 min, purity =100%; Factor XIa Ki = 3,300 nM.

Example 329

(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- manufacture of onion

MS(ESI) m/z: 633.1 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.21 (s, 1H), 8.82 (s, 1H), 8.64 (d, J=4.9 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.71 - 7.64 (m, 4H), 7.59 (d, J=4.9 Hz, 1H), 7.53 - 7.44 (m, 4H), 6.26 (s, 1H), 5.88 (d, J=9.8 Hz, 1H), 4.01 (s, 3H), 2.68 - 2.59 (m, 1H), 2.32 - 2.24 (m, 1H), 2.15 - 2.06 (m, 1H), 1.86 - 1.77 (m, 1H), 1.51 - 1.42 (m, 1H) , 1.38 - 1.28 (m, 1H), 0.88 (d, J=6.7 Hz, 3H), 0.48 - 0.32 (m, 1H); Analytical HPLC (Method A): RT =2.09 min, purity =100%; Factor XIa Ki = 380 nM.

Example 330

(9R,13S)-13-(4-{5-chloro-2-[4-(propan-2-ylsulfanyl)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl )-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] octadeca-1(18),2(6),4,14,16-pentaene- Preparation of 8-one

MS(ESI) m/z: 639.1 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.15 (s, 1H), 8.80 (s, 1H), 8.62 (d, J=5.2 Hz, 1H), 7.65 (d, J=2.1 Hz, 1H), 7.60 (s, 1H), 7.57 - 7.52 (m, 2H), 7.43 - 7.38 (m, 2H), 7.25 (d, J=7.9 Hz, 2H), 7.12 (d, J=8.2 Hz, 2H), 6.08 (s, 1H), 5.82 (d, J=9.8 Hz, 1H), 3.96 (s, 3H), 3.49 - 3.39 (m, 1H), 2.62 - 2.55 (m, 1H), 2.27 - 2.17 (m, 1H) ), 2.10 - 2.01 (m, 1H), 1.81 - 1.72 (m, 1H), 1.46 - 1.36 (m, 1H), 1.33 - 1.23 (m, 1H), 1.18 (dd, J=6.6, 2.0 Hz, 6H ), 0.83 (d, J=7.0 Hz, 3H), 0.42 - 0.28 (m, 1H); Analytical HPLC (Method A): RT =2.25 min, purity =100%; Factor XIa Ki = 400 nM.

Example 331

4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzene-1-sulfone Preparation of amides

MS(ESI) m/z: 644 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.21 (s, 1H), 8.85 (s, 1H), 8.69 (d, J=5.2 Hz, 1H), 7.78 (d, J=8.2 Hz, 2H), 7.73 (d, J=2.1 Hz, 1H), 7.67 - 7.64 (m, 2H), 7.58 (d, J=5.2 Hz, 1H), 7.52 - 7.40 (m, 6H), 6.25 (s, 1H), 5.89 (d, J=10.7 Hz, 1H), 4.01 (s, 3H), 2.68 - 2.60 (m, 1H), 2.33 - 2.24 (m, 1H), 2.15 - 2.06 (m, 1H), 1.88 - 1.78 (m , 1H), 1.51 - 1.42 (m, 1H), 1.39 - 1.28 (m, 1H), 0.88 (d, J=6.7 Hz, 3H), 0.48 - 0.33 (m, 1H); Analytical HPLC (Method A): RT =1.54 min, purity =100%; Factor XIa Ki = 130 nM.

Example 332

(9R,13S)-13-(4-{5-chloro-2-[4-(difluoromethoxy)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- manufacture of onion

MS(ESI) m/z: 631 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.21 (s, 1H), 8.86 (s, 1H), 8.67 (d, J=4.9 Hz, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.65 (s, 1H), 7.63 - 7.57 (m, 2H), 7.49 - 7.42 (m, 2H), 7.31 - 7.26 (m, 3H), 7.17 - 7.11 (m, 2H), 6.17 (s, 1H), 5.88 (d, J=9.8 Hz, 1H), 4.01 (s, 3H), 2.69 - 2.60 (m, 1H), 2.34 - 2.24 (m, 1H), 2.16 - 2.06 (m, 1H), 1.88 - 1.79 ( m, 1H), 1.51 - 1.42 (m, 1H), 1.39 - 1.28 (m, 1H), 0.88 (d, J=6.7 Hz, 3H), 0.48 - 0.33 (m, 1H); Analytical HPLC (Method A): RT =1.97 min, purity =100%; Factor XIa Ki = 180 nM.

Example 333

N-[3-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)phenyl] Preparation of methanesulfonamide

MS(ESI) m/z: 658 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.20 (s, 1H), 8.87 (s, 1H), 8.69 (d, J=5.2 Hz, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.66 - 7.60 (m, 3H), 7.58 (d, J=5.2 Hz, 1H), 7.48 - 7.44 (m, 2H), 7.38 - 7.33 (m, 1H), 7.16 (dd, J=8.1, 1.1 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 7.03 (s, 1H), 6.10 (s, 1H), 5.86 (d, J=9.8 Hz, 1H), 4.01 (s, 3H), 2.80 ( s, 3H), 2.70 - 2.60 (m, 1H), 2.34 - 2.24 (m, 1H), 2.15 - 2.05 (m, 1H), 1.88 - 1.78 (m, 1H), 1.51 - 1.42 (m, 1H), 1.39 - 1.28 (m, 1H), 0.89 (d, J=7.0 Hz, 3H), 0.49 - 0.35 (m, 1H); Analytical HPLC (Method A): RT =1.68 min, purity =100%; Factor XIa Ki = 1,200 nM.

Example 334

3-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzonitrile

MS(ESI) m/z: 590.3 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.21 (s, 1H), 8.78 (s, 1H), 8.68 (d, J=5.2 Hz, 1H), 7.80 (dd, J=5.3, 2.3 Hz, 1H ), 7.74 - 7.70 (m, 2H), 7.68 - 7.64 (m, 2H), 7.59 - 7.51 (m, 4H), 7.47 (s, 1H), 6.31 (s, 1H), 5.86 (d, J=10.4 Hz, 1H), 4.01 (s, 3H), 2.70 - 2.59 (m, 1H), 2.33 - 2.23 (m, 1H), 2.14 - 2.04 (m, 1H), 1.86 - 1.77 (m, 1H), 1.51 - 1.41 (m, 1H), 1.38 - 1.28 (m, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.50 - 0.36 (m, 1H); Analytical HPLC (Method A): RT =1.8 min, purity =100%; Factor XIa Ki = 1,600 nM.

Example 335

(9R,13S)-13-(4-{5-chloro-2-[3-(trifluoromethoxy)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2, 6]octadeca-1(18),2(6),4,14,16-pentaene-8- manufacture of onion

MS(ESI) m/z: 649 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.20 (s, 1H), 8.84 (s, 1H), 8.67 (d, J=5.2 Hz, 1H), 7.69 (d, J=2.1 Hz, 1H), 7.67 - 7.62 (m, 2H), 7.58 (d, J=5.2 Hz, 1H), 7.52 (dt, J=8.1, 3.9 Hz, 2H), 7.47 (s, 1H), 7.36 (d, J=7.9 Hz) , 1H), 7.32 (d, J=8.2 Hz, 1H), 7.09 (s, 1H), 6.23 (s, 1H), 5.88 (d, J=10.4 Hz, 1H), 4.00 (s, 3H), 2.69 - 2.60 (m, 1H), 2.33 - 2.24 (m, 1H), 2.14 - 2.05 (m, 1H), 1.82 - 1.72 (m, 1H), 1.51 - 1.41 (m, 1H), 1.37 - 1.27 (m, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.49 - 0.36 (m, 1H); Analytical HPLC (Method A): RT =2.13 min, purity =100%; Factor XIa Ki = 3,700 nM.

Example 336

(9R,13S)-13-{4-[5-chloro-2-(3-methanesulfonylphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9 -Preparation of dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 643 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.24, 9.21 (s, 1H), 9.02, 8.79 (2s, 1H), 8.71 - 8.63 (m, J=14.0, 4.9 Hz, 1H), 8.17 - 7.43 ( m, 9H), 7.07, 6.32 (2s, 1H), 5.99 - 5.78 (m, 1H), 4.01 (d, J=1.8 Hz, 3H), 3.91, 3.11 (2s, 3H), 2.70 - 2.59 (m, 1H), 2.41 - 2.21 (m, 1H), 2.18 - 2.04 (m, 1H), 1.99 - 1.75 (m, 1H), 1.54 - 1.26 (m, 2H), 0.93 - 0.85 (m, 3H), 0.55 - 0.35 (m, 1H); Analytical HPLC (Method A): RT =1.65 min, purity =100%; Factor XIa Ki = 1,200 nM.

Example 337

Methyl 4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] Preparation of octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzoate

MS(ESI) m/z: 623.1 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.14 (s, 1H), 8.74 (s, 1H), 8.60 (d, J=4.9 Hz, 1H), 7.84 (d, J=8.2 Hz, 2H), 7.66 (d, J=2.1 Hz, 1H), 7.60 - 7.56 (m, 2H), 7.51 (d, J=5.2 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.31 (d, J=8.2 Hz) , 2H), 6.12 (s, 1H), 5.82 - 5.75 (m, 1H), 3.94 (s, 3H), 3.80 (s, 3H), 2.61 - 2.53 (m, 1H), 2.26 - 2.16 (m, 1H) ), 2.09 - 1.97 (m, 1H), 1.80 - 1.71 (m, 1H), 1.44 - 1.19 (m, 2H), 0.81 (d, J=6.7 Hz, 3H), 0.42 - 0.25 (m, 1H); Analytical HPLC (Method A): RT =1.91 min, purity =98.6%; Factor XIa Ki = 750 nM.

Example 338

(9R,13S)-13-{4-[5-chloro-2-(3-methylphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl- Preparation of 3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 579.1 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.22 (s, 1H), 8.86 (s, 1H), 8.68 (d, J=5.2 Hz, 1H), 7.68 (d, J=2.1 Hz, 1H), 7.65 (s, 1H), 7.62 - 7.56 (m, 2H), 7.47 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.24 - 7.18 (m, 1H), 7.13 (d, J= 7.6 Hz, 1H), 7.05 (s, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.09 (s, 1H), 5.85 (d, J=10.4 Hz, 1H), 4.01 (s, 3H) , 2.67 - 2.60 (m, 1H), 2.35 - 2.22 (m, 4H), 2.14 - 2.05 (m, 1H), 1.88 - 1.78 (m, 1H), 1.51 - 1.42 (m, 1H), 1.38 - 1.28 ( m, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.51 - 0.37 (m, 1H); Analytical HPLC (Method A): RT =2.03 min, purity =100%; Factor XIa Ki = 1,400 nM.

Example 339

4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octa Preparation of deca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzonitrile

MS(ESI) m/z: 590.1 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.22 (s, 1H), 8.79 (s, 1H), 8.67 (d, J=4.9 Hz, 1H), 7.80 (d, J=8.2 Hz, 2H), 7.73 (d, J=2.1 Hz, 1H), 7.69 - 7.64 (m, 2H), 7.59 (d, J=5.2 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 7.47 (s, 1H) ), 7.43 (d, J=8.5 Hz, 2H), 6.29 (s, 1H), 5.87 (d, J=10.1 Hz, 1H), 4.01 (s, 3H), 2.69 - 2.60 (m, 1H), 2.33 - 2.23 (m, 1H), 2.15 - 2.06 (m, 1H), 1.87 - 1.78 (m, 1H), 1.52 - 1.42 (m, 1H), 1.38 - 1.28 (m, 1H), 0.88 (d, J= 6.7 Hz, 3H), 0.49 - 0.33 (m, 1H); Analytical HPLC (Method A): RT =1.8 min, purity =100%; Factor XIa Ki = 290 nM.

Example 340

(9R,13S)-13-{4-[5-chloro-2-(1-methyl-1H-indol-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl }-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene- Preparation of 8-one

MS(ESI) m/z: 618.1 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.20 (s, 1H), 8.90 (s, 1H), 8.68 (d, J=5.2 Hz, 1H), 7.72 (d, J=2.1 Hz, 1H), 7.61 (s, 1H), 7.60 - 7.55 (m, 2H), 7.47 - 7.43 (m, 3H), 7.39 - 7.33 (m, 2H), 6.96 (dd, J=8.5, 1.2 Hz, 1H), 6.40 ( d, J=3.1 Hz, 1H), 5.98 (s, 1H), 5.82 (d, J=10.7 Hz, 1H), 4.00 (s, 3H), 3.79 (s, 3H), 2.66 - 2.59 (m, 1H) ), 2.33 - 2.24 (m, 1H), 2.13 - 2.03 (m, 1H), 1.85 - 1.77 (m, 1H), 1.49 - 1.40 (m, 1H), 1.37 - 1.27 (m, 1H), 0.87 (d , J=7.0 Hz, 3H), 0.45 - 0.32 (m, 1H); Analytical HPLC (Method A): RT =2.02 min, purity=100%; Factor XIa Ki = 1,300 nM.

Example 341

(9R,13S)-13-{4-[5-chloro-2-(isoquinolin-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9 -Preparation of dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 616 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.48 (d, J=16.8 Hz, 1H), 9.17 (s, 1H), 8.66 - 8.58 (m, 2H), 8.43 (br. s., 1H), 8.24 (t, J=9.3 Hz, 1H), 7.90 (t, J=1.8 Hz, 1H), 7.82 - 7.69 (m, 3H), 7.56 - 7.51 (m, 2H), 7.48 (dd, J=8.2, 3.4 Hz, 1H), 7.45 - 7.38 (m, 2H), 6.00 (d, J=9.5 Hz, 1H), 5.69 (d, J=10.4 Hz, 1H), 3.99 (s, 3H), 2.63 - 2.57 ( m, 1H), 2.19 - 1.96 (m, 2H), 1.73 - 1.59 (m, 1H), 1.45 - 1.34 (m, 1H), 1.31 - 1.20 (m, 1H), 0.85 (d, J=5.2 Hz, 3H), 0.41 - 0.28 (m, 1H); Analytical HPLC (Method B): RT =1.32 min, purity =100%; Factor XIa Ki = 6,500 nM.

Example 342

Methyl 3-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ] Preparation of octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)benzoate

MS(ESI) m/z: 623.2 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.21 (s, 1H), 8.80 (s, 1H), 8.65 (d, J=5.2 Hz, 1H), 7.93 - 7.89 (m, 1H), 7.79 (s , 1H), 7.71 (d, J=2.1 Hz, 1H), 7.66 - 7.63 (m, 2H), 7.58 (d, J=5.2 Hz, 1H), 7.54 - 7.46 (m, 4H), 6.23 (s, 1H), 5.86 (d, J=9.8 Hz, 1H), 4.01 (s, 3H), 3.78 (s, 3H), 2.67 - 2.59 (m, 1H), 2.31 - 2.22 (m, 1H), 2.14 - 2.05 (m, 1H), 1.83 - 1.74 (m, 1H), 1.51 - 1.41 (m, 1H), 1.37 - 1.27 (m, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.50 - 0.36 (m , 1H); Analytical HPLC (Method A): RT =1.87 min, purity =100%; Factor XIa Ki = 2,200 nM.

Example 343

N-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2, 6} ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)phenyl] Preparation of methanesulfonamide

MS(ESI) m/z: 657.9 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.21 (s, 1H), 8.86 (s, 1H), 8.70 (d, J=5.2 Hz, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.65 (s, 1H), 7.62 - 7.56 (m, 2H), 7.50 - 7.42 (m, 2H), 7.30 - 7.25 (m, 1H), 7.22 - 7.14 (m, 4H), 6.11 (s, 1H), 5.86 (d, J=8.9 Hz, 1H), 4.01 (s, 3H), 2.99 (s, 3H), 2.68 - 2.61 (m, 1H), 2.34 - 2.23 (m, 1H), 2.16 - 2.06 (m, 1H), 1.88 - 1.78 (m, 1H), 1.53 - 1.28 (m, 2H), 0.88 (d, J=7.0 Hz, 3H), 0.51 - 0.33 (m, 1H); Analytical HPLC (Method B): RT =1.63 min, purity =97.8%; Factor XIa Ki = 450 nM.

Example 344

(9R,13S)-13-(4-{5-chloro-2-[3-(trifluoromethyl)phenyl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)- 3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene-8- manufacture of onion

MS(ESI) m/z: 633 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.21 (s, 1H), 8.79 (s, 1H), 8.65 (d, J=5.2 Hz, 1H), 7.73 - 7.64 (m, 4H), 7.61 - 7.54 (m, 4H), 7.52 - 7.46 (m, 2H), 6.30 (s, 1H), 5.86 (d, J=10.4 Hz, 1H), 4.01 (s, 3H), 2.67 - 2.59 (m, 1H), 2.33 - 2.23 (m, 1H), 2.14 - 2.05 (m, J=12.1, 12.1 Hz, 1H), 1.82 - 1.73 (m, 1H), 1.50 - 1.41 (m, 1H), 1.37 - 1.27 (m, 1H) ), 0.88 (d, J=6.7 Hz, 3H), 0.52 - 0.38 (m, 1H); Analytical HPLC (Method A): RT =2.06 min, purity =100%; Factor XIa Ki = 4,800 nM.

Example 345

(9R,13S)-13-{4-[5-chloro-2-(4-methoxyphenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9- Preparation of dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 595 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.22 (s, 1H), 8.89 (s, 1H), 8.69 (d, J=5.2 Hz, 1H), 7.68 - 7.64 (m, 2H), 7.60 - 7.56 (m, 2H), 7.47 (s, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.9 Hz, 2H), 6.08 (s, 1H), 5.87 (d, J=10.1 Hz, 1H), 4.01 (s, 3H), 3.76 (s, 3H), 2.68 - 2.60 (m, 1H), 2.34 - 2.26 (m, 1H), 2.16 - 2.06 (m, 1H), 1.89 - 1.79 (m, 1H), 1.51 - 1.42 (m, 1H), 1.39 - 1.28 (m, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.48 - 0.35 (m, 1H); Analytical HPLC (Method A): RT =1.89 min, purity =100%; Factor XIa Ki = 350 nM.

Example 346

(9R,13S)-13-{4-[5-chloro-2-(4-chlorophenyl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl Preparation of -3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 599 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.22 (s, 1H), 8.85 (s, 1H), 8.68 (d, J=4.9 Hz, 1H), 7.70 (d, J=2.1 Hz, 1H), 7.66 (s, 1H), 7.63 (dd, J=8.2, 2.1 Hz, 1H), 7.59 (d, J=5.2 Hz, 1H), 7.48 - 7.44 (m, 2H), 7.40 (d, J=8.5 Hz) , 2H), 7.25 (d, J=8.2 Hz, 2H), 6.19 (s, 1H), 5.88 (d, J=9.8 Hz, 1H), 4.01 (s, 3H), 2.69 - 2.60 (m, 1H) , 2.34 - 2.25 (m, 1H), 2.15 - 2.06 (m, 1H), 1.88 - 1.79 (m, 1H), 1.52 - 1.42 (m, 1H), 1.39 - 1.28 (m, 1H), 0.88 (d, J=6.7 Hz, 3H), 0.49 - 0.34 (m, 1H); Analytical HPLC (Method B): RT =2 min, purity =95.5%; Factor XIa Ki = 220 nM.

Example 347

(9R,13S)-13-{4-[5-chloro-2-(pyridin-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9- Preparation of dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 566.1 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.21 (s, 1H), 8.80 (s, 1H), 8.68 (d, J=5.2 Hz, 1H), 8.55 (d, J=5.8 Hz, 2H), 7.74 (d, J=1.8 Hz, 1H), 7.69 (dd, J=8.2, 2.1 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J=5.2 Hz, 1H), 7.53 (d, J =8.2 Hz, 1H), 7.47 (s, 1H), 7.30 (d, J=5.8 Hz, 2H), 6.34 (s, 1H), 5.87 (d, J=10.7 Hz, 1H), 4.01 (s, 3H) ), 2.69 - 2.60 (m, 1H), 2.33 - 2.23 (m, 1H), 2.15 - 2.06 (m, 1H), 1.88 - 1.78 (m, 1H), 1.52 - 1.42 (m, 1H), 1.38 - 1.28 (m, 1H), 0.88 (d, J=7.0 Hz, 3H), 0.48 - 0.35 (m, 1H); Analytical HPLC (Method A): RT =1.52 min, purity =98.9%; Factor XIa Ki = 2,000 nM.

Example 348

(9R,13S)-13-{4-[5-chloro-2-(isoquinolin-7-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9 -Preparation of dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 616 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.25 (d, J=7.3 Hz, 2H), 8.73 (s, 1H), 8.60 (d, J=5.2 Hz, 1H), 8.50 (d, J=5.8 Hz, 1H), 8.03 (s, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.86 (d, J=5.5 Hz, 1H), 7.75 (d, J=1.8 Hz, 1H), 7.70 - 7.66 (m, 1H), 7.63 - 7.56 (m, 3H), 7.53 (d, J=4.9 Hz, 1H), 7.45 (s, 1H), 6.22 (s, 1H), 5.82 - 5.74 (m, 1H) , 3.98 (s, 3H), 2.66 - 2.59 (m, 1H), 2.25 - 2.16 (m, 1H), 2.07 - 1.99 (m, 1H), 1.83 - 1.74 (m, 1H), 1.48 - 1.38 (m, 1H), 1.35 - 1.25 (m, 1H), 0.85 (d, J=7.0 Hz, 3H), 0.47 - 0.32 (m, 1H); Analytical HPLC (Method A): RT =1.77 min, purity =94.8%; Factor XIa Ki = 260 nM, plasma kallikrein Ki = 3,600 nM.

Example 349

(9R,13S)-13-{4-[5-chloro-2-(pyrimidin-5-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9 -Preparation of dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaen-8-one

MS(ESI) m/z: 567 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.22 (s, 1H), 9.16 (s, 1H), 8.80 (s, 1H), 8.71 - 8.66 (m, 3H), 7.79 (d, J=2.1 Hz) , 1H), 7.73 (dd, J=8.2, 1.8 Hz, 1H), 7.67 (s, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.58 (d, J=4.9 Hz, 1H), 7.48 (s, 1H), 6.46 (s, 1H), 5.89 (d, J=10.4 Hz, 1H), 4.02 (s, 3H), 2.69 - 2.61 (m, 1H), 2.33 - 2.23 (m, 1H), 2.16 - 2.07 (m, J=13.7 Hz, 1H), 1.87 - 1.78 (m, 1H), 1.52 - 1.43 (m, 1H), 1.38 - 1.28 (m, 1H), 0.89 (d, J=6.7 Hz, 3H), 0.48 - 0.35 (m, 1H); Analytical HPLC (Method A): RT =1.4 min, purity =100%; Factor XIa Ki = 16 nM, plasma kallikrein Ki = 3,000 nM.

Example 350

Ethyl 2-[4-(4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0 ^{2 ,6} ]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,6-dihydropyrimidin-4-yl}phenyl)- Preparation of 1H-pyrazol-1-yl]acetate

MS(ESI) m/z: 631.1 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.25 (s, 1H), 8.84 (s, 1H), 8.67 (d, J=5.2 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.66 - 7.46 (m, 6H), 7.43 - 7.38 (m, 1H), 7.16 - 7.11 (m, 2H), 7.00 (br. s., 1H), 6.20 (s, 1H), 5.89 - 5.82 (m, 1H), 4.01 (s, 3H), 2.68 - 2.60 (m, 1H), 2.33 - 2.23 (m, 1H), 2.13 - 2.04 (m, J=7.0 Hz, 1H), 1.86 - 1.77 (m, 1H) , 1.52 - 1.42 (m, 1H), 1.38 - 1.28 (m, 1H), 0.89 (d, J=6.7 Hz, 3H), 0.51 - 0.37 (m, 1H); Analytical HPLC (Method A): RT =1.99 min, purity =96.9%; Factor XIa Ki = 600 nM.

Example 351

(9R,13S)-13-{4-[5-chloro-2-(1-ethyl-1H-pyrazol-4-yl)phenyl]-6-oxo-1,6-dihydropyrimidine-1- 1}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4,14,16-pentaene Preparation of -8-one

MS(ESI) m/z: 583.1 (M+H) ⁺ ;

¹ H NMR (400MHz, CD ₃ OD) δ 8.98 (s, 1H), 8.75 (d, J=5.1 Hz, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.56 - 7.52 (m, 2H), 7.49 (s, 1H), 7.48 - 7.47 (m, 2H), 7.36 (s, 1H), 6.39 (s, 1H), 6.02 (dd, J=12.7, 4.3 Hz, 1H), 4.12 (q , J=7.3 Hz, 2H), 4.05 (s, 3H), 2.76 - 2.67 (m, 1H), 2.39 - 2.29 (m, 1H), 2.14 - 2.00 (m, 2H), 1.67 - 1.43 (m, 2H) ), 1.37 (t, J=7.3 Hz, 3H), 1.01 (d, J=6.8 Hz, 3H), 0.79 - 0.64 (m, 1H); Analytical HPLC (Method A): RT =1.55 min, purity =95.5%; Factor XIa Ki = 96 nM.

Example 352

(9R,13S)-13-(4-{5-chloro-2-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,6-di Hydropyrimidin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo [12.3.1.0 ^2,6 ]octadeca-1(18),2(6),4, Preparation of 14,16-pentaen-8-one

MS(ESI) m/z: 649.3 (M+H) ⁺ ;

^1H NMR (500MHz, DMSO-d ₆ ) δ 9.24 (s, 1H), 8.95 (s, 1H), 8.62 (d, J=5.2 Hz, 1H), 8.53 (s, 1H), 7.83 (dd, J =8.9, 4.6 Hz, 2H), 7.70 (s, 1H), 7.67 - 7.56 (m, 5H), 7.49 (s, 1H), 7.36 (t, J=8.7 Hz, 2H), 6.46 (s, 1H) , 5.96 (d, J=10.7 Hz, 1H), 4.03 (s, 3H), 2.70 - 2.62 (m, 1H), 2.38 - 2.28 (m, 1H), 2.18 - 2.10 (m, 1H), 1.94 - 1.85 (m, 1H), 1.54 - 1.45 (m, 1H), 1.41 - 1.31 (m, 1H), 0.90 (d, J=6.7 Hz, 3H), 0.51 - 0.38 (m, 1H); Analytical HPLC (Method A): RT =1.99 min, purity =100%; Factor XIa Ki = 7 nM.

Claims (1)

Uses of Compounds.